Hepatitis c virus inhibitors

ABSTRACT

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/286,178 filed Dec. 14, 2009. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel antiviral agents. Morespecifically, the present invention relates to compounds which caninhibit the function of the NS5A protein encoded by Hepatitis C virus(HCV), compositions comprising such compounds, methods for inhibitingHCV viral replication, methods for treating or preventing HCV infection,and processes for making the compounds.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughoutthe world. In the US, an estimated 4.5 million Americans are chronicallyinfected with HCV. Although only 30% of acute infections aresymptomatic, greater than 85% of infected individuals develop chronic,persistent infection. Treatment costs for HCV infection have beenestimated at $5.46 billion for the US in 1997. Worldwide over 200million people are estimated to be infected chronically. HCV infectionis responsible for 40-60% of all chronic liver disease and 30% of allliver transplants. Chronic HCV infection accounts for 30% of allcirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDCestimates that the number of deaths due to HCV will minimally increaseto 38,000/year by the year 2010.

Due to the high degree of variability in the viral surface antigens,existence of multiple viral genotypes, and demonstrated specificity ofimmunity, the development of a successful vaccine in the near future isunlikely. Alpha-interferon (alone or in combination with ribavirin) hasbeen widely used since its approval for treatment of chronic HCVinfection. However, adverse side effects are commonly associated withthis treatment: flu-like symptoms, leukopenia, thrombocytopenia,depression from interferon, as well as anemia induced by ribavirin(Lindsay, K. L. (1997) Hepatology 26 (suppl 1): 71S-77S). This therapyremains less effective against infections caused by HCV genotype 1(which constitutes ˜75% of all HCV infections in the developed markets)compared to infections caused by the other 5 major HCV genotypes.Unfortunately, only ˜50-80% of the patients respond to this treatment(measured by a reduction in serum HCV RNA levels and normalization ofliver enzymes) and, of responders, 50-70% relapse within 6 months ofcessation of treatment. Recently, with the introduction of pegylatedinterferon (Peg-IFN), both initial and sustained response rates haveimproved substantially, and combination treatment of Peg-IFN withribavirin constitutes the gold standard for therapy. However, the sideeffects associated with combination therapy and the impaired response inpatients with genotype 1 present opportunities for improvement in themanagement of this disease.

First identified by molecular cloning in 1989 (Choo, Q-L et al (1989)Science 244:359-362), HCV is now widely accepted as the most commoncausative agent of post-transfusion non-A, non-B hepatitis (NANBH) (Kuo,G et al (1989) Science 244:362-364). Due to its genome structure andsequence homology, this virus was assigned as a new genus in theFlaviviridae family. Like the other members of the Flaviviridae, such asflaviviruses (e.g. yellow fever virus and Dengue virus types 1-4) andpestiviruses (e.g. bovine viral diarrhea virus, border disease virus,and classic swine fever virus) (Choo, Q-L et al (1989) Science244:359-362; Miller, R. H. and R. H. Purcell (1990) Proc. Natl. Acad.Sci. USA 87:2057-2061), HCV is an enveloped virus containing a singlestrand RNA molecule of positive polarity. The HCV genome isapproximately 9.6 kilobases (kb) with a long, highly conserved,noncapped 5′ nontranslated region (NTR) of approximately 340 bases whichfunctions as an internal ribosome entry site (IRES) (Wang C Y et al ‘AnRNA pseudoknot is an essential structural element of the internalribosome entry site located within the hepatitis C virus 5′ noncodingregion’ RNA—A Publication of the RNA Society. 1(5): 526-537, 1995 July).This element is followed by a region which encodes a single long openreading frame (ORF) encoding a polypeptide of ˜3000 amino acidscomprising both the structural and nonstructural viral proteins.

Upon entry into the cytoplasm of the cell, this RNA is directlytranslated into a polypeptide of ˜3000 amino acids comprising both thestructural and nonstructural viral proteins. This large polypeptide issubsequently processed into the individual structural and nonstructuralproteins by a combination of host and virally-encoded proteinases (Rice,C. M. (1996) in B. N. Fields, D. M. Knipe and P. M. Howley (eds)Virology 2^(nd) Edition, p931-960; Raven Press, N.Y.). There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are severalnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease. NS5A is a membrane-anchored phosphoprotein that isobserved in basally phosphorylated (56 kDa) and hyperphosphorylated (58kDa) forms. While its function has not fully been elucidated, NS5A isbelieved to be important in viral replication. The NS5B protein (591amino acids, 65 kDa) of HCV (Behrens, S. E. et al (1996) EMBO J. 1512-22), encodes an RNA-dependent RNA polymerase (RdRp) activity andcontains canonical motifs present in other RNA viral polymerases. TheNS5B protein is fairly well conserved both intra-typically (˜95-98%amino acid (aa) identity across 1b isolates) and inter-typically (˜85%aa identity between genotype 1a and 1b isolates). The essentiality ofthe HCV NS5B RdRp activity for the generation of infectious progenyvirions has been formally proven in chimpanzees (A. A. Kolykhalov et al.(2000) Journal of Virology, 74(4): 2046-2051). Thus, inhibition of NS5BRdRp activity (inhibition of RNA replication) is predicted to be usefulto treat HCV infection.

Following the termination codon at the end of the long ORF, there is a3′ NTR which roughly consists of three regions: an ˜40 base region whichis poorly conserved among various genotypes, a variable lengthpoly(U)/polypyrimidine tract, and a highly conserved 98 base elementalso called the “3′ X-tail” (Kolykhalov, A. et al (1996) J. Virology70:3363-3371; Tanaka, T. et al (1995) Biochem Biophys. Res. Commun.215744-749; Tanaka, T. et al (1996) J. Virology 70:3307-3312; Yamada, N.et al (1996) Virology 223:255-261). The 3′ NTR is predicted to form astable secondary structure which is essential for HCV growth in chimpsand is believed to function in the initiation and regulation of viralRNA replication.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in Tan, S.-L.,Katzel, M. G. Virology 2001, 284, 1; and in Rice, C. M. Nature 2005,435, 374.

Based on the foregoing, there exists a significant need to identifycompounds with the ability to inhibit HCV.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds representedherein below, pharmaceutical compositions comprising such compounds, andmethods for the treatment or prophylaxis of viral (particularly HCV)infection in a subject in need of such therapy with said compounds.Compounds of the present invention interfere with the life cycle of thehepatitis C virus and are also useful as antiviral agents.

In its principal aspect, the present invention provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Ring A and Ring B are each independently absent or a monocyclic orpolycyclic group independently selected from aryl, heteroaryl,heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionallysubstituted; preferably, optionally substituted aryl or optionallysubstituted heteroaryl;

L is absent or selected from the group consisting of optionallysubstituted C₁-C₄ alkyl, optionally substituted C₂-C₄ alkenyl, andoptionally substituted C₂-C₄ alkynyl;

wherein at least one of Ring A, Ring B and L is present;

G and J are each independently an optionally substituted 5-memberedheteroaryl or optionally substituted 5/6-membered fused heteroaryl,wherein the 5-membered heteroaryl contains one or more nitrogen atoms,and wherein the 6-membered ring of said 5/6-membered fused heteroaryl isattached to one of Ring A, L and Ring B and is aryl or heteroaryl;preferably, optionally substituted imidazolyl, optionally substitutedbenzimidazolyl or optionally substituted imidazopyridyl;

X is independently N—OR¹, N—N(R¹)₂, or C(R²)₂; preferably, CH₂, CF₂ orN-OMe;

R¹ at each occurence is independently hydrogen or optionally substitutedC₁-C₄ alkyl;

R² at each occurence is independently hydrogen, halogen, optionallysubstituted C₁-C₄ alkyl, optionally substituted aryl, or optionallysubstituted heteroaryl; alternatively, two R² groups can be takentogether with the carbon atom to which they are attached to form anoptionally substituted C₃-C₈ cycloalkyl or optionally substitutedheterocyclic ring;

R⁶ at each occurence is independently selected from the group consistingof optionally substituted O(C₁-C₈ alkyl), optionally substituted amino,C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionallysubstituted; preferably, optionally substituted C₁-C₈ alkyl; morepreferably, C₁-C₈ alkyl optionally substituted with amino, hydroxy,protected amino or O(C₁-C₄ alkyl);

Q is selected from:

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₈ alkyl, optionally substitutedC₂-C₈ alkenyl, and optionally substituted C₃-C₈ cycloalkyl; preferably,hydrogen or optionally substituted C₁-C₄ alkyl; alternatively, R³ and R⁴can be taken together with the carbon atom to which they are attached toform optionally substituted C₃-C₈ cycloalkyl or optionally substitutedheterocyclic;

R⁵ is independently hydrogen, optionally substituted C₁-C₈ alkyl, oroptionally substituted C₃-C₈ cycloalkyl; preferably, hydrogen oroptionally substituted C₁-C₄ alkyl;

U is absent or independently selected from O, S, S(O), SO₂, NC(O)—(C₁-C₄alkyl), C(O), protected carbonyl, OCH₂, OCH₂CH₂, SCH₂, SCH₂CH₂, C(R⁷)₂,C(R⁷)₂C(R⁷)₂, or C═C(R²)₂; in an additional embodiment, U is selectedfrom O, S, S(O), SO₂, NC(O)—(C₁-C₄ alkyl), C(O), protected carbonyl,OCH₂, OCH₂CH₂, SCH₂, SCH₂CH₂, C(R⁷)₂, C(R⁷)₂C(R⁷)₂, C═C(R²)₂, C═N—O(R¹)and C═N—N(R¹)₂; in yet an additional embodiment, U is selected from O,S, S(O), SO₂, NC(O)—(C₁-C₄ alkyl), C(O), OCH₂, OCH₂CH₂, SCH₂, SCH₂CH₂,C(R⁷)₂, C(R⁷)₂C(R⁷)₂, C═C(R²)₂, C═N—O(R¹) and C═N—N(R¹)₂; preferably, Uis CH₂, C═N—OR¹, or C═C(R²)₂;

In one embodiment, R⁷ at each occurrence is independently selected fromthe group consisting of hydrogen, halogen, cyano, hydroxy, O(C₁-C₄alkyl), S(C₁-C₄ alkyl), amino optionally substituted with one or twoC₁-C₄ alkyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted C₁-C₄ alkyl; preferably hydrogen,halogen, hydroxyl; in another embodiment, R⁷ at each occurrence isindependently selected from the group consisting of hydrogen, halogen,cyano, hydroxy, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), amino optionallysubstituted with one or two C₁-C₄ alkyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted C₃-C₈cycloalkyl and optionally substituted C₁-C₄ alkyl; preferably hydrogen,halogen, hydroxyl. or optionally substituted cyclopropyl;

Alternatively two geminal R⁷ groups can be taken together with thecarbon atom to which they are attached to form a spiro, optionallysubstituted C₃-C₇ cycloalkyl, spiro, optionally substituted C₃-C₇cycloalkenyl or spiro, optionally substituted, 3- to 7-memberedheterocyclic ring; preferably, spiro cyclopropyl;

R^(7a) and R^(7b) at each occurrence are each independently selectedfrom the group consisting of hydrogen, optionally substituted aryl, andoptionally substituted C₁-C₄ alkyl; preferably, hydrogen or methyl;

Alternatively, CHR^(7a)—U or CHR^(7b)—U can be taken together to form agroup selected from CH═CH, fused and optionally substituted C₃-C₈cycloalkyl, fused and optionally substituted aryl, or fused andoptionally substituted heterocyclic; preferably fused, optionallysubstituted cyclopropyl; and

Yet alternatively, U, R^(7a), and R^(7b) can be taken together with thecarbon atoms to which they are attached to form a bridged, optionallysubstituted 4- to 7-membered ring selected from the group consisting ofC₄-C₇ cycloalkyl, C₄-C₇ cycloalkenyl and 4- to 7-membered heterocyclic;preferably, bridged cyclopentyl.

Each preferred group stated above can be taken in combination with one,any or all other preferred groups.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier or excipient.

In yet another aspect, the present invention provides a method ofinhibiting the replication of a RNA-containing virus comprisingcontacting said virus with said pharmaceutical composition.Particularly, this invention is directed to methods of inhibiting thereplication of HCV.

In still another aspect, the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising administering to a patient in need of such treatment withsaid pharmaceutical composition. Particularly, this invention isdirected to methods of treating or preventing infection caused by HCV.

Yet another aspect of the present invention provides the use of acompound or combination of compounds of the present invention, or atherapeutically acceptable salt thereof, as defined hereinafter, in thepreparation of a medicament for the treatment or prevention of infectioncaused by RNA-containing virus, specifically HCV.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of Formula (I) as illustratedabove, or pharmaceutically acceptable salts thereof.

The compounds of the invention have utility in inhibiting thereplication of RNA-containing virus, including, for example, HCV. Othercompounds useful for inhibiting the replication of RNA-containingviruses and/or for the treatment or prophylaxis of HCV infection havebeen described in copending U.S. application Ser. No. 12/702,673 filedFeb. 9, 2010 entitled “Linked Dibenzimidiazole Derivatives”; U.S.application Ser. No. 12/702,692 filed Feb. 9, 2010 entitled “LinkedDibenzimidiazole Derivatives”; U.S. application Ser. No. 12/702,802filed Feb. 9, 2010 entitled “Linked Dibenzimidiazole Derivatives”; U.S.application Ser. No. 12/707,190 filed Feb. 17, 2010 entitled “LinkedDiimidazole Antivirals”; U.S. application Ser. No. 12/707,200 filed Feb.17, 2010 entitled “Linked Diimidazole Derivatives”; U.S. applicationSer. No. 12/707,210 filed Feb. 17, 2010 entitled “Hepatitis C VirusInhibitors”; U.S. application Ser. No. 12/714,583 filed Mar. 1, 2010entitled “Novel Benzimidazole Derivatives”; and U.S. application Ser.No. 12/714,576 filed Mar. 1, 2010 entitled “Hepatitis C VirusInhibitors”; U.S. application Ser. No. 12/816,148 filed Jun. 15, 2010entitled “Hepatitis C Virus Inhibitors”; U.S. application Ser. No.12/816,171 filed Jun. 15, 2010 entitled “Hepatitis C Virus Inhibitors”;U.S. application Ser. No. 12/879,025 filed Sep. 10, 2010 entitled“Hepatitis C Virus Inhibitors”; U.S. application Ser. No. 12/879,026filed Sep. 10, 2010 entitled “Hepatitis C Virus Inhibitors”; U.S.application Ser. No. 12/879,027 filed Sep. 10, 2010 entitled “HepatitisC Virus Inhibitors”; U.S. application Ser. No. 12/879,028 filed Sep. 10,2010 entitled “Hepatitis C Virus Inhibitors”; U.S. application Ser. No.12/879,029 filed Sep. 10, 2010 entitled “Hepatitis C Virus Inhibitors”;U.S. application Ser. No. 12/879,031 filed Sep. 10, 2010 entitled“Hepatitis C Virus Inhibitors”; U.S. Provisional Application Ser. No.61/297,918 filed Jan. 25, 2010 entitled “Hepatitis C Virus Inhibitors”;U.S. Provisional Application Ser. No. 61/314,304 filed Mar. 16, 2010entitled “Hepatitis C Virus Inhibitors”; U.S. Provisional ApplicationSer. No. 61/322,438 filed Apr. 9, 2010 entitled “Hepatitis C VirusInhibitors”; U.S. Provisional Application Ser. No. 61/351,327 filed Jun.4, 2010 entitled “Hepatitis C Virus Inhibitors”; U.S. ProvisionalApplication Ser. No. 61/372,999 filed Aug. 12, 2010 entitled “HepatitisC Virus Inhibitors”; and the contents of each of which are expresslyincorporated by reference herein.

As discussed above, a general strategy for the development of antiviralagents is to inactivate virally encoded proteins, including NS5A, thatare essential for the replication of the virus. The relevant patentdisclosures describing the synthesis of HCV NS5A inhibitors are: US2009/0202478; US 2009/0202483; US 2010/0233120; US 2010/0260708; WO2004/014852; WO 2006/079833; WO 2006/133326; WO 2007/031791; WO2007/070556; WO 2007/070600; WO 2007/082554; WO 2008/021927; WO2008/021928; WO 2008/021936; WO 2008/048589; WO 2008/064218; WO2008/070447; WO 2008/144380; WO 2008/154601; WO 2009/020825; WO2009/020828; WO 2009/034390; WO 2009/102318; WO 2009/102325; WO2009/102694; WO 2010/017401; WO 2010/039793; WO 2010/065668; WO2010/065674; WO 2010/065681; WO 2010/091413; WO 2010/096777; WO2010/096462; WO 2010/096302; WO 2010/111483; WO 2010/111534; WO2010/117635; WO 2010/111673; WO 2010/117704; WO 2010/132538; WO2010/132601; WO 2010/138488; WO 2010/138368; WO 2010/138790; and WO2010/138791, the contents of each of which are expressly incorporated byreference herein.

In another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein X isC(R²)₂ or N—OR¹.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein X isCH₂, CF₂, or N-OMe.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein G andJ are each independently optionally substituted five-membered heteroarylcontaining one or more nitrogen atoms, and are each C-attached.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein G andJ are each independently optionally substituted 5/6-membered ring fusedheteroaryl, wherein the 5-membered ring of said 5/6-membered fusedheteroaryl is a heteroaryl containing one or more nitrogen atoms andwherein the 5-membered ring is C-attached, and wherein the 6-memberedring of said 5/6-membered fused heteroaryl is aryl or heteroaryl and isC-attached to one of Ring A, L and Ring B.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein oneof G and J is an optionally substituted five-membered heteroarylcontaining one or more nitrogen atoms, and is C-attached; the other oneof G and J is an optionally substituted 5/6-membered fused heteroaryl;wherein the 5-membered ring of said 5/6-membered fused heteroaryl is aheteroaryl containing one or more nitrogen atoms and wherein the5-membered ring is C-attached, and wherein the 6-membered ring of said5/6-membered fused heteroaryl is aryl or heteroaryl and is C-attached toone of Ring A, L and Ring B.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein L isabsent, Ring A and Ring B are each independently optionally substitutedphenyl, monocyclic heteroaryl, naphthyl, or bicyclic heteroaryl.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein L isoptionally substituted C₂-C₄ alkenyl or optionally substituted C₂-C₄alkynyl; and wherein one of Ring A and Ring B is absent, and the otherof Ring A and Ring B is independently optionally substituted phenyl,monocyclic heteroaryl, naphthyl, or bicyclic heteroaryl.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein G andJ are each independently illustrated by one of the following heteroarylgroups:

wherein each of the above shown heteroaryl groups is optionallysubstituted.

In yet another embodiment, the present invention relates to compounds ofFormula (I), or pharmaceutically acceptable salts thereof; wherein G andJ are each independently optionally substituted imidazolyl,benzimidazolyl or imidazopyridyl.

In yet another embodiment, the present invention relates to compounds ofFormulae (Ia-1˜Ia-2), or pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, U, X, R¹, R³, R⁴, R⁵, R⁶, R^(7a) andR^(7b) are as previously defined.

In yet another embodiment, the present invention relates to compounds ofFormulae (Ia-3˜Ia-4), or pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, U, X, R⁶, and R^(7b) are as previouslydefined.

In yet another embodiment, the present invention relates to compounds ofFormulae (Ia-5˜Ia-6), or pharmaceutically acceptable salts thereof:

wherein Ring A, Ring B, G, J, L, U, X, R⁶, and R^(7b) are as previouslydefined.

In yet another embodiment, the present invention relates to compounds ofFormulae (Ia-5˜Ia-6), or pharmaceutically acceptable salts thereof;wherein R⁶ at each occurrence is selected from the group consisting ofC₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formula (Ia-5˜Ia-6), or pharmaceutically acceptable salts thereof;wherein R⁶ at each occurrence is independently C₁-C₈ alkyl optionallysubstituted with amino, hydroxy, protected amino, or O(C₁-C₄ alkyl).

In still another embodiment, the present invention relates to compoundsof Formulae (Ib-1˜Ib-5), or pharmaceutically acceptable salts thereof:

wherein G, J, Q, X, R¹, R⁶, R^(7a), and R^(7b) are as previouslydefined; in Formula (Ib-4), Ring A, Ring B and L are each present and aspreviously defined; in Formula (Ib-1), Ring A and Ring B are eachpresent and as previously defined; in Formula (Ib-2), Ring B and L areeach present and as previously defined; in Formula (Ib-3), Ring A and Lare each present and as previously defined; and in Formula (Ib-5), RingB is present and as previously defined.

In still another embodiment, the present invention relates to compoundsof Formulae (Ib-1˜Ib-5), or pharmaceutically acceptable salts thereof;wherein R⁶ is C₁-C₈ alkyl optionally substituted with amino, hydroxy,protected amino or O(C₁-C₄ alkyl).

In still another embodiment, the present invention relates to compoundsof Formula (Ib-1), or pharmaceutically acceptable salts thereof; whereinRing A and Ring B are each independently optionally substituted phenylor monocyclic heteroaryl; and G and J are each independently optionallysubstituted imidazolyl.

In still another embodiment, the present invention relates to compoundsof Formula (Ib-1), or pharmaceutically acceptable salts thereof; whereinRing A and Ring B are each independently optionally substituted phenylor monocyclic heteroaryl; and G and J are each independently optionallysubstituted benzimidazolyl or optionally substituted imidazopyridyl.

In still another embodiment, the present invention relates to compoundsof Formula (Ib-1), or pharmaceutically acceptable salts thereof; whereinone of Ring A and Ring B is optionally substituted phenyl or optionallysubstituted monocyclic heteroaryl, the other of Ring A and Ring B isoptionally substituted bicyclic aryl or bicyclic heteroaryl; and G and Jare each independently imidazolyl, benzimidazolyl or imidazopyridyl,each optionally substituted.

In still another embodiment, the present invention relates to compoundsof Formula (Ib-1), or pharmaceutically acceptable salts thereof; whereinRing A and Ring B are each independently optionally substituted bicyclicaryl or bicyclic heteroaryl; and G and J are each independentlyoptionally substituted imidazolyl.

In still another embodiment, the present invention relates to compoundsof Formula (Ib-2˜Ib-3), or pharmaceutically acceptable salts thereof;wherein Ring B or Ring A is optionally substituted phenyl or monocyclicheteroaryl; L is optionally substituted C₂-C₄ alkenyl or optionallysubstituted C₂-C₄ alkynyl; and G and J are each independentlyimidazolyl, benzimidazolyl or imidazopyridyl, each optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formulae (Ib-2˜Ib-3), or pharmaceutically acceptable salts thereof;wherein Ring B or Ring A is optionally substituted bicyclic aryl orbicyclic heteroaryl; L is optionally substituted C₂-C₄ alkenyl oroptionally substituted C₂-C₄ alkynyl; and G and J are each independentlyimidazolyl, benzimidazolyl or imidazopyridyl, each optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formula (Ib-4), or pharmaceutically acceptable salts thereof; whereinRing A and Ring B are each independently optionally substituted phenylor monocyclic heteroaryl; L is optionally substituted C₂-C₄ alkenyl oroptionally substituted C₂-C₄ alkynyl; and G and J are each independentlyimidazolyl, benzimidazolyl or imidazopyridyl, each optionallysubstituted.

In still another embodiment, the present invention relates to compoundsof Formula (Ib-5), or pharmaceutically acceptable salts thereof; whereinRing B is independently optionally substituted polycyclic aryl orheteroaryl; and G and J are each independently imidazolyl,benzimidazolyl or imidazopyridyl, each optionally substituted.

In another embodiment, the present invention relates to compounds ofFormulae (Ic-1) and (Ic-2) below,

and pharmaceutically acceptable salts thereof, wherein each R, R′, R″and R″′ is independently H, halogen, optionally substituted C₁-C₆-alkyl,optionally substituted C₁-C₆-alkoxy, or optionally substitutedC₁-C₆-alkyl-C(O)— and Q, X, R¹, R⁶, R^(7a) and R^(7b) are as previouslydefined in Formula (I). In a preferred embodiment, each of R, R′, R″ andR′″ is H; in another preferred embodiment, each of R, R′, R″ and R′″ isindependently selected from H, chloro, fluoro, trifluoromethyl, methoxyand acetyl. In yet another embodiment, the present invention relates tocompounds of Formulae (Ic-1i) and (Ic-2i):

and pharmaceutically acceptable salts thereof, wherein each R, R′, R″,R′″Q, X, R¹, R⁶, R^(7a) and R^(7b) are as previously defined in Formulae(Ic-1) and (Ic-2).

In another embodiment, the present invention relates to compounds ofFormula (Ic-3),

and pharmaceutically acceptable salts thereof, wherein Q, X, R¹, R⁶,R^(7a) and R^(7b) are as previously defined in Formula (I) and A^(a) isselected from the groups set forth below.

In an additional aspect, the invention relates to compounds of Formula(Ic-3i):

and pharmaceutically acceptable salts thereof, wherein Q, X, R¹, R⁶,R^(7a), R^(7b) and A^(a) are as previously defined in Formula (Ic-3).

In another embodiment, the present invention relates to compounds ofFormula (Ic-4),

and pharmaceutically acceptable salts thereof, wherein Q, X, R¹, R⁶,R^(7a) and R^(7b) are as previously defined in Formula (I) and A^(a) isselected from the groups set forth below.

In yet an additional aspect, the present invention relates to compoundsof Formula (Ic-4i):

or pharmaceutically acceptable salts thereof, wherein Q, X, R¹, R⁶,R^(7a), R^(7b) and A^(a) are as previously defined in Formula (Ic-4).

In still another embodiment, the present invention relates to compoundsof Formula (Ic-5):

and pharmaceutically acceptable salts thereof, wherein Q, X, R¹, R⁶,R^(7a) and R^(7b) are as previously defined in Formula (I) and Gg isselected from the groups set forth below.

In an additional aspect, the present invention relates to compounds ofFormula (Ic-5i):

and pharmaceutically acceptable salts thereof, wherein Q, X, R¹, R⁶,R^(7a), R^(7b) and G^(g) are as previously defined in Formula (Ic-5).

In still another embodiment, the present invention relates to compoundsof Formulae (I), (Ia-1) to (Ia-6), (Ib-1) to (Ib-5), (Ic-1) to (Ic-5),and (Ic-1i) to (Ic-5i), and pharmaceutically acceptable salts thereof;wherein

at each occurrence is one of the following groups:

Representative compounds of the present invention are those selectedfrom compounds 1-337 compiled in the following tables:

TABLE 1 Compounds 1-219.

Entry

 1

 2

 3

 4

 5

 6

 7

 8

 9

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 11

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TABLE 2 Compounds 220-229.

Entry R R′ R″ U Entry R R′ R″ U 220 Me H H CH₂ 221 H H H CF₂ 222 Me H HS 223 H H H

224 H Me H CH₂ 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

TABLE 3 Compounds 230-239.

Entry R R′ R″ Entry R R′ R″ 230 Me H H 231 H CO₂Me H 232 H F H 233 H HCO₂Me 234 H H F 235 H OMe H 236 H Cl H 237 H H OMe 238 H H Cl 239 H CF₃H

TABLE 4 Compounds 240-249.

Entry R R′ R″ R′′′ Entry R R′ R″ R′′′ 240 F H H H 241 F F H H 242 Me H HH 243 Me Me H H 244 H H Me Me 245 H H Et Et 246 CF₃ H H H 247 CF₃ H CF H248 Cl H H H 249 Cl H Cl H

TABLE 5 Compounds 250-264.

Entry R Entry R Entry R 250

251

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264

TABLE 6 Compounds 265-282.

Entry A^(a) Entry A^(a) Entry A^(a) 265

266

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TABLE 7 Compounds 283-303.

Entry A^(a) Entry A^(a) Entry A^(a) 283

284

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TABLE 8 Compounds 304-315.

Entry G^(g) Entry G^(g) Entry G^(g) 304

305

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315

TABLE 9 Compounds 316-337 316

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337

It will be appreciated that the description of the present inventionherein should be construed in congruity with the laws and principals ofchemical bonding. In some instances it may be necessary to remove ahydrogen atom in order to accommodate a substitutent at any givenlocation.

It is intended that the definition of any substituent or variable (e.g.,R³, R⁷, etc.) at a particular location in a molecule be independent ofits definitions elsewhere in that molecule. For example, when X isC(R⁷)₂, each of the two R⁷ groups may be the same or different.

It will be yet appreciated that the compounds of the present inventionmay contain one or more asymmetric carbon atoms and may exist inracemic, diastereoisomeric, and optically active forms. It will still beappreciated that certain compounds of the present invention may exist indifferent tautomeric forms. All tautomers are contemplated to be withinthe scope of the present invention.

It should be understood that in some embodiments, the compoundsencompassed by the present invention are those that are suitably stablefor use as pharmaceutical agent.

It will be further appreciated that reference herein to therapy and/ortreatment includes, but is not limited to, prevention, retardation,prophylaxis, therapy and/or cure of the disease. It will further beappreciated that references herein to treatment or prophylaxis of HCVinfection includes treatment or prophylaxis of HCV-associated diseasesuch as liver fibrosis, cirrhosis and hepatocellular carcinoma.

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound a combination of two or morecompounds delineated herein, or a pharmaceutically acceptable saltthereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound or a combination of two ormore compounds delineated herein, or a pharmaceutically acceptable saltthereof, in combination with one or more agents known in the art, with apharmaceutically acceptable carrier or excipient.

It will be further appreciated that compounds of the present inventioncan be administered as the sole active pharmaceutical agent, or used incombination with one or more agents to treat or prevent hepatitis Cinfections or the symptoms associated with HCV infection. Other agentsto be administered in combination with a compound or combination ofcompounds of the present invention include therapies for disease causedby HCV infection that suppresses HCV viral replication by direct orindirect mechanisms. These agents include, but are not limited to, hostimmune modulators (for example, interferon-alpha, pegylatedinterferon-alpha, consensus interferon, interferon-beta,interferon-gamma, CpG oligonucleotides and the like); antiviralcompounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase (for example, ribavirin and the like);cytokines that modulate immune function (for example, interleukin 2,interleukin 6, and interleukin 12); a compound that enhances thedevelopment of type 1 helper T cell response; interfering RNA;anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvantcombinations directed against HCV; agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like; and any agent or combination ofagents that inhibit the replication of HCV by targeting other proteinsof the viral genome involved in the viral replication and/or interferewith the function of other viral targets, such as inhibitors of NS3/NS4Aprotease, NS3 helicase, NS5B polymerase, NS4A protein and NS5A protein.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise other inhibitor(s) of targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, NS4A protein, NS5A protein, and internalribosome entry site (IRES).

Accordingly, one embodiment of the present invention is directed to amethod for treating or preventing an infection caused by anRNA-containing virus comprising co-administering to a patient in need ofsuch treatment one or more agents selected from the group consisting ofa host immune modulator and a second or more antiviral agents, or acombination thereof, with a therapeutically effective amount of acompound or combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. Examples of the host immunemodulator include, but are not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome. Example of theRNA-containing virus includes, but not limited to, hepatitis C virus(HCV).

A further embodiment of the present invention is directed to a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment anagent or combination of agents that treat or alleviate symptoms of HCVinfection including cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt thereof. Example of the RNA-containing virus includes, but notlimited to, hepatitis C virus (HCV).

Yet another embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. An agent that treats patientsfor disease caused by hepatitis B (HBV) infection may be for example,but not limited thereto, L-deoxythymidine, adefovir, lamivudine ortenfovir, or any combination thereof. Example of the RNA-containingvirus includes, but not limited to, hepatitis C virus (HCV).

A further embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by humanimmunodeficiency virus (HIV) infection, with a therapeutically effectiveamount of a compound or a combination of compounds of the presentinvention, or a pharmaceutically acceptable salt thereof. The agent thattreats patients for disease caused by human immunodeficiency virus (HIV)infection includes, but is not limited thereto, ritonavir, lopinavir,indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or anycombination thereof. Example of the RNA-containing virus includes, butis not limited to, hepatitis C virus (HCV).

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated is combination therapy to treat suchco-infections by co-administering a compound according to the presentinvention with at least one of an HIV inhibitor, an HAV inhibitor and anHBV inhibitor.

In addition, the present invention provides the use of a compound or acombination of compounds of the invention, or a therapeuticallyacceptable salt thereof, and one or more agents selected from the groupconsisting of a host immune modulator and a second or more antiviralagents, or a combination thereof, to prepare a medicament for thetreatment of an infection caused by an RNA-containing virus in apatient, particularly hepatitis C virus. Examples of the host immunemodulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compounds orcompounds of the present invention, together with one or more agents asdefined herein above, can be employed in pure form or, where such formsexist, in pharmaceutically acceptable salt thereof. Alternatively, suchcombination of therapeutic agents can be administered as apharmaceutical composition containing a therapeutically effective amountof the compound or combination of compounds of interest, or theirpharmaceutically acceptable salt thereof, in combination with one ormore agents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, a still further embodiment of the invention is directed to amethod of treating or preventing infection caused by an RNA-containingvirus, particularly a hepatitis C virus (HCV), comprising administeringto a patient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt thereof, and one or more agents asdefined hereinabove, with a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other agents to be administered in combination with a compound of thepresent invention include a cytochrome P450 monooxygenase inhibitor(also referred to herein as a CYP inhibitor), which is expected toinhibit metabolism of the compounds of the invention. Therefore, thecytochrome P450 monooxygenase inhibitor would be in an amount effectiveto inhibit metabolism of the compounds of this invention. Accordingly,the CYP inhibitor is administered in an amount such that thebioavailiablity of the protease inhibitor is increased in comparison tothe bioavailability in the absence of the CYP inhibitor.

In one embodiment, the invention provides methods for improving thepharmacokinetics of compounds of the invention. The advantages ofimproving the pharmacokinetics of drugs are recognized in the art (see,for example, US Patent Pub. Nos. 2004/0091527; US 2004/0152625; and US2004/0091527). Accordingly, one embodiment of this invention provides amethod for administering an inhibitor of CYP3A4 and a compound of theinvention. Another embodiment of this invention provides a method foradministering a compound of the invention and an inhibitor of isozyme3A4 (“CYP3A4”), isozyme 2C19 (“CYP2C19”), isozyme 2D6 (“CYP2D6”),isozyme 1A2 (“CYP1A2”), isozyme 2C9 (“CYP2C9”), or isozyme 2E1(“CYP2E1”). In a preferred embodiment, the CYP inhibitor preferablyinhibits CYP3A4. Any CYP inhibitor that improves the pharmacokinetics ofthe relevant NS3/4A protease may be used in a method of this invention.These CYP inhibitors include, but are not limited to, ritonavir (see,for example, WO 94/14436), ketoconazole, troleandomycin,4-methylpyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole,fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone,sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir,saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.Preferred CYP inhibitors include ritonavir, ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole.

It will be understood that the administration of the combination of theinvention by means of a single patient pack, or patient packs of eachformulation, containing within a package insert instructing the patientto the correct use of the invention is a desirable additional feature ofthis invention.

According to a further aspect, the invention is a pack comprising atleast a compound of the invention and a CYP inhibitor of the inventionand an information insert containing directions on the use of thecombination of the invention. In an alternative embodiment of thisinvention, the pharmaceutical pack further comprises one or more ofadditional agent as described herein. The additional agent or agents maybe provided in the same pack or in separate packs.

Another aspect of this involves a packaged kit for a patient to use inthe treatment of HCV infection or in the prevention of HCV infection,comprising: a single or a plurality of pharmaceutical formulation ofeach pharmaceutical component; a container housing the pharmaceuticalformulation (s) during storage and prior to administration; andinstructions for carrying out drug administration in a manner effectiveto treat or prevent HCV infection.

Accordingly, this invention provides kits for the simultaneous orsequential administration of a compound of the invention and a CYPinhibitor (and optionally an additional agent) or derivatives thereofare prepared in a conventional manner. Typically, such a kit willcomprise, e.g. a composition of each inhibitor and optionally theadditional agent (s) in a pharmaceutically acceptable carrier (and inone or in a plurality of pharmaceutical formulations) and writteninstructions for the simultaneous or sequential administration.

In another embodiment, a packaged kit is provided that contains one ormore dosage forms for self administration; a container means, preferablysealed, for housing the dosage forms during storage and prior to use;and instructions for a patient to carry out drug administration. Theinstructions will typically be written instructions on a package insert,a label, and/or on other components of the kit, and the dosage form orforms are as described herein. Each dosage form may be individuallyhoused, as in a sheet of a metal foil-plastic laminate with each dosageform isolated from the others in individual cells or bubbles, or thedosage forms may be housed in a single container, as in a plasticbottle. The present kits will also typically include means for packagingthe individual kit components, i.e., the dosage forms, the containermeans, and the written instructions for use. Such packaging means maytake the form of a cardboard or paper box, a plastic or foil pouch, etc.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication. Viralinfection may be determined by measuring virus antibody titer in samplesof a biological fluid, such as blood, using, e.g., enzyme immunoassay.Other suitable diagnostic methods include molecular based techniques,such as RT-PCR, direct hybrid capture assay, nucleic acid sequence basedamplification, and the like. A virus may infect an organ, e.g., liver,and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease andhepatocellular carcinoma.

The term “immune modulator” refers to any substance meant to alter theworking of the humoral or cellular immune system of a subject. Suchimmune modulators include inhibitors of mast cell-mediated inflammation,interferons, interleukins, prostaglandins, steroids, cortico-steroids,colony-stimulating factors, chemotactic factors, etc.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, idenyl. A polycyclic aryl is a polycyclicring system that comprises at least one aromatic ring. Polycyclic arylscan comprise fused rings, covalently attached rings or a combinationthereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicring system comprising at least one aromatic ring having one or morering atom selected from S, O and N; and the remaining ring atoms arecarbon, wherein any N or S contained within the ring may be optionallyoxidized. Heteroaryl includes, but is not limited to, pyridinyl,pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl.A polycyclic heteroaryl can comprise fused rings, covalently attachedrings or a combination thereof.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and they can be fused or covalently attached.

The term “tricyclic aryl” or “tricyclic heteroaryl” refers to a ringsystem consisting of three rings wherein at least one ring is aromatic.

The terms “C₁-C₄ alkyl,” “C₁-C₆ alkyl,” “C₁-C₈ alkyl,” “C₂-C₄ alkyl,” or“C₃-C₆ alkyl,” as used herein, refer to saturated, straight- orbranched-chain hydrocarbon radicals containing between one and four, oneand six, one and eight carbon atoms, or the like, respectively. Examplesof C₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl andoctyl radicals.

The terms “C₂-C₈ alkenyl,” “C₂-C₄ alkenyl,” “C₃-C₄ alkenyl,” or “C₃-C₆alkenyl,” as used herein, refer to straight- or branched-chainhydrocarbon radicals containing from two to eight, or two to four carbonatoms, or the like, having at least one carbon-carbon double bond by theremoval of a single hydrogen atom. Alkenyl groups include, but are notlimited to, for example, ethenyl, propenyl, butenyl,1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The terms “C₂-C₈ alkynyl,” “C₂-C₄ alkynyl,” “C₃-C₄ alkynyl,” or “C₃-C₆alkynyl,” as used herein, refer to straight- or branched-chainhydrocarbon radicals containing from two to eight, or two to four carbonatoms, or the like, having at least one carbon-carbon triple bond by theremoval of a single hydrogen atom. Representative alkynyl groupsinclude, but are not limited to, for example, ethynyl, 1-propynyl,1-butynyl, heptynyl, octynyl, and the like.

The term “C₃-C₈-cycloalkyl”, or “C₅-C₇-cycloalkyl,” as used herein,refers to a monocyclic or polycyclic saturated carbocyclic ringcompound, and the carbon atoms may be optionally oxo-substituted.Examples of C₃-C₈-cycloalkyl include, but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; andexamples of C₅-C₇-cycloalkyl include, but not limited to, cyclopentyl,cyclohexyl, bicyclo [2.2.1] heptyl, and the like.

The term “C₃-C₈ cycloalkenyl” or “C₅-C₇ cycloalkenyl” as used herein,refers to monocyclic or polycyclic carbocyclic ring compound having atleast one carbon-carbon double bond and the carbon atoms may beoptionally oxo-substituted. Examples of C₃-C₈ cycloalkenyl include, butnot limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples ofC₅-C₇ cycloalkenyl include, but not limited to, cyclopentenyl,cyclohexenyl, cycloheptenyl, and the like.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can also be an aliphatic group oran alicyclic group. An “aliphatic” group is a non-aromatic moiety thatmay contain any combination of carbon atoms, hydrogen atoms, halogenatoms, oxygen, nitrogen or other atoms, and optionally contains one ormore units of unsaturation, e.g., double and/or triple bonds, andincludes and/or optionally contains one or more functional groups, e.g.,0, OH, NH, NH₂, C(O), S(O)₂, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂,S(O)₂NH, S(O)₂NH₂, NHC(O)NH₂, or the like, and the carbon atoms may beoptionally oxo-substituted. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, as used herein, aliphaticgroups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls,such as polyalkylene glycols, polyamines, and polyimines, for example.Such aliphatic groups may be further substituted. A linear aliphaticgroup is an aliphatic group that comprised of only non-cyclic aliphaticgroup.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom, and the carbon atoms may beoptionally oxo-substituted. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [2.2.1]heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may be furthersubstituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused system, where (i) each ring system contains atleast one heteroatom independently selected from oxygen, sulfur andnitrogen, (ii) each ring system can be saturated or unsaturated (iii)the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to an aromatic ring and (vi) the remaining ring atomsare carbon atoms which may be optionally oxo-substituted. Representativeheterocycloalkyl groups include, but are not limited to, 1,3-dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, andtetrahydrofuryl. Such heterocyclic groups may be further substituted.Heteroaryl or heterocyclic groups can be C-attached or N-attached (wherepossible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent group whenused as a linkage to connect two groups or substituents, which can be atthe same or different atom(s).

The term “substituted” when used with alkyl, alkenyl, alkynyl,alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, oraliphatic as described herein refers to substitution by independentreplacement of one, two, or three or more of the hydrogen atoms thereonwith substituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo,—NH—C₁-C₁₂-alkyl, —NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl, —CONH—C₂-C₈-alkynyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₈-alkenyl,—OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —CO₂—C₁-C₁₂ alkyl, —CO₂—C₂-C₈alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl, —CO₂— aryl,CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH— heterocycloalkyl, —NHC(O)H,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl,—NHCO₂—C₂-C₈-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₈-alkenyl,—NHC(O)NH—C₂-C₈-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₈-alkenyl,—NHC(S)NH—C₂-C₈-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₈-alkenyl,—NHC(NH)NH—C₂-C₈-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH— heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “carbonyl protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a carbonyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the carbonyl protecting group as described hereinmay be selectively removed. Carbonyl protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of carbonyl protecting groups include acetals,ketals, cyclic acetals, cyclic ketals, mono- or dithioacetals, mono- ordithioketals, optionally substituted hydrazones or oximes.

The term “protected carbonyl,” as used herein, refers to a carbonylgroup protected with a carbonyl protecting group, as defined above,including dimethyl acetal, 1,3-dioxolane, 1,3-dioxane,S,S′-dimethylketal, 1,3-dithiane, 1,3-dithiolane, 1,3-oxathiolane,N,N-dimethylhydrazone, oxime, for example.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “substituted amino,” as used herein, refers to substitution byreplacement of one or two hydrogen atoms of —NH₂ with substituentsindependently selected from the group consisting of optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedcycloalkyl, optionally substituted heteroaryl, and optionallysubstituted heterocyclic; alternatively, when disubstituted, the twosubstitutents can be optionally taken together with the nitrogen atom towhich they are attached to form an optionally substituted heterocyclicgroup.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; hydroxy; imidazolyl; and acyloxy groups, such asacetoxy, trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protic solvent’ as used herein, refers to a solvent that tendsto provide protons, such as an alcohol, for example, methanol, ethanol,propanol, isopropanol, butanol, t-butanol, and the like. Such solventsare well known to those skilled in the art, and it will be obvious tothose skilled in the art that individual solvents or mixtures thereofmay be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)— or (S)—, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The present invention also relates to solvates of the compounds ofFormula (I), for example hydrates.

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminum hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings and other coatings well known in thepharmaceutical formulating art. They may optionally contain opacifyingagents and can also be of a composition that they release the activeingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al. and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969incorporated herein by reference.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 0.1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a patient such as a human oranother animal by administering to the subject a therapeuticallyeffective amount of a compound of the invention, in such amounts and forsuch time as is necessary to achieve the desired result. An additionalmethod of the present invention is the treatment of biological sampleswith an inhibitory amount of a compound of composition of the presentinvention in such amounts and for such time as is necessary to achievethe desired result.

The term “therapeutically effective amount” of a compound of theinvention, as used herein, means an amount of the compound which confersa therapeutic effect on the treated subject, at a reasonablebenefit/risk ratio applicable to any medical treatment. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect).

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the viral load in a biologicalsample or a subject (e.g., resulting in at least 10%, preferably atleast 50%, more preferably at least 80%, and most preferably at least90% or 95%, reduction in viral load). It is understood that when saidinhibitory amount of a compound of the present invention is administeredto a subject it will be at a reasonable benefit/risk ratio applicable toany medical treatment as determined by a physician. The term “biologicalsample(s),” as used herein, means a substance of biological originintended for administration to a subject. Examples of biological samplesinclude, but are not limited to, blood and components thereof such asplasma, platelets, subpopulations of blood cells and the like; organssuch as kidney, liver, heart, lung, and the like; sperm and ova; bonemarrow and components thereof; or stem cells. Thus, another embodimentof the present invention is a method of treating a biological sample bycontacting said biological sample with an inhibitory amount of acompound or pharmaceutical composition of the present invention.

Effective doses will also vary depending on route of administration, aswell as the possibility of co-usage with other agents. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcontemporaneously with the specific compound employed; and like factorswell known in the medical arts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the Formula (I) described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(eg ribavirin and amantadine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Combination and Alternation Therapy for HCV

It has been recognized that drug-resistant variants of HCV can emergeafter prolonged treatment with an antiviral agent. Drug resistance mosttypically occurs by mutation of a gene that encodes for a protein suchas an enzyme used in viral replication, and most typically in the caseof HCV, RNA polymerase, protease, or helicase.

Recently, it has been demonstrated that the efficacy of a drug against aviral infection, such as HIV, can be prolonged, augmented, or restoredby administering the drug in combination or alternation with a second,and perhaps third, antiviral compound that induces a different mutationfrom that caused by the principal drug. Alternatively, thepharmacokinetics, biodistribution, or other parameter of the drug can bealtered by such combination or alternation therapy. In general,combination therapy is typically preferred over alternation therapybecause it induces multiple simultaneous stresses on the virus.

A compound of the present invention can also be administered incombination or alternation with antiviral agent. Examplary antiviralagents include ribavarin, interferon, interleukin or a stabilizedprodrug of any of them. More broadly described, the compound can beadministered in combination or alternation with any of the anti-HCVdrugs listed in Table 10 below.

TABLE 10 Table of anti-Hepatitis C Compounds in Current ClinicalDevelopment Drug name Drug category Pharmaceutical Company PEGASYS Longacting interferon Roche pegylated interferon alfa-2a INFERGEN Longacting interferon InterMune interferon alfacon-1 OMNIFERON Long actinginterferon Viragen natural interferon ALBUFERON Long acting interferonHuman Genome Sciences REBIF interferon beta-la Interferon Ares-SeronoOmega Interferon Interferon BioMedicine Oral Interferon alpha OralInterferon Amarillo Biosciences Interferon gamma-lb Anti-fibroticInterMune IP-501 Anti-fibrotic InterMune Merimebodib VX-497 IMPDHinhibitor Vertex (inosine monophosphate dehydrogenase) AMANTADINE(Symmetrel) Broad Antiviral Agent Endo Labs Solvay IDN-6556 Apotosisregulation Idun Pharma. XTL-002 Monclonal Antibody XTL HCV/MF59 VaccineChiron CIVACIR Polyclonal Antibody NABI Innogenetics Therapeutic vaccineVIRAMIDINE Nucleoside Analogue ICN ZADAXIN (thymosin alfa-1)Immunomodulator Sci Clone CEPLENE (histamine) Immunomodulator Maxim VX950/LY 570310 Protease inhibitor Vertex/Eli Lilly ISIS 14803 AntisenseIsis Pharmaceutical/Elan IDN-6556 Caspase inhibitor Idun PharmaceuticalsJTK 003 Polymerase Inhibitor AKROS Pharma Tarvacin Anti-PhospholipidTherapy Peregrine HCV-796 Polymerase Inhibitor ViroPharma/Wyeth CH-6Protease inhibitor Schering ANA971 Isatoribine ANADYS ANA245 IsatoribineANADYS CPG 10101 (Actilon) Immunomodulator Coley Rituximab (Rituxam)Anti-CD2O Genetech/IDEC Monoclonal Antibody NM283 (Valopicitabine)Polymerase Inhibitor Idenix Pharmaceuticals HepX ™-C Monoclonal AntibodyXTL IC41 Therapeutic Vaccine Intercell Medusa Interferon Longer actinginterferon Flamel Technology E-1 Therapeutic Vaccine InnogeneticsMultiferon Long Acting Interferon Viragen BILN 2061 Protease inhibitorBoehringer-Ingelheim TMC435350 Protease inhibitor Tibotec/MedivirTelaprevir (VX-950) Protease inhibitor Vertex Boceprevir (SCH 503034)Protease inhibitor Schering-Plough ACH-1625 Protease inhibitor AchillionABT-450 Protease inhibitor Abbott/Enanta BI-201335 Protease inhibitorBoehringer-Ingelheim PHX-1766 Protease inhibitor Phenomix VX-500Protease inhibitor Vertex MK-7009 protease inhibitor Merck R7227(ITMN-191) protease inhibitor InterMune Narlaprevir (SCH 900518)Protease inhibitor Schering/Merck Alinia (nitazoxanide) To be determinedRomark ABT-072 Polymerase Inhibitor Abbott ABT-333 Polymerase InhibitorAbbott Filibuvir (PF-00868554) Polymerase Inhibitor Pfizer VCH-916Polymerase Inhibitor Vertex R7128 (PSI6130) Polymerase InhibitorRoche/Pharmasset IDX184 Polymerase Inhibitor Idenix IDX-189 PolymeraseInhibitor Inhibitex PSI-7977 Polymerase Inhibitor Pharmasset PSI-938Polymerase Inhibitor Pharmasset R1626 Polymerase inhibitor Roche MK-3281Polymerase inhibitor Merck PSI-7851 Polymerase inhibitor PharmassetANA598 Polymerase inhibitor Anadys Pharmaceuticals BI-207127 Polymeraseinhibitor Boehringer-Ingelheim GS-9190 Polymerase inhibitor GileadVCH-759 Polymerase Inhibitor Vertex Clemizole NS4B inhibitor EigerBiopharmaceuticals A-832 NS5A inhibitor ArrowTherapeutics BMS-790052NS5A inhibitor Bristol-Myers-Squibb BMS-824393 NS5A inhibitorBristol-Myers-Squibb GS-5885 NS5A inhibitor Gilead ITX5061 Entryinhibitor iTherx GS-9450 Caspase inhibitor Gilead ANA773 TLR agonistAnadys CYT107 immunomodulator Cytheris SPC3649 (LNA-antimiR ™-122)microRNA Santaris Pharma Debio 025 Cyclophilin inhibitor DebiopharmSCY-635 Cyclophilin inhibitor Scynexis

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBNfor azobisisobutyronitrile; BINAP for2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O fordi-tert-butyl-dicarbonate; Boc for t-butoxycarbonyl; Bpoc for1-methyl-1-(4-biphenylyl)ethyl carbonyl; BtOH for1-hydroxy-benzotriazole; Bz for benzoyl; Bn for benzyl; BocNHOH fortert-butyl N-hydroxycarbamate; t-BuOK for potassium tert-butoxide;Bu₃SnH for tributyltin hydride; BOP for(benzotriazol-1-yloxy)tris(dimethylamino)phos-phoniumHexafluorophosphate; Brine for sodium chloride solution in water; Cbzfor carbobenzyloxy; CDI for carbonyldiimidazole; CH₂Cl₂ fordichloromethane; CH₃ for methyl; CH₃CN for acetonitrile; Cs₂CO₃ forcesium carbonate; CuCl for copper (I) chloride; CuI for copper (I)iodide; dba for dibenzylidene acetone; dppb for diphenylphosphinobutane; DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC forN,N′-dicyclohexylcarbodiimide; DEAD for diethylazodicarboxylate; DIADfor diisopropyl azodicarboxylate; DIPEA or (i-Pr)₂EtN forN,N-diisopropylethyl amine; Dess-Martin periodinane for1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one; DMAP for4-dimethylaminopyridine; DME for 1,2-dimethoxy-ethane; DMF forN,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT fordi(p-methoxyphenyl)phenylmethyl or dimethoxytrityl; DPPA fordiphenylphosphoryl azide; EDC forN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide; EDC HCl forN-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride; EtOAc forethyl acetate; EtOH for ethanol; Et₂O for diethyl ether; Fmoc for9-fluorenylmethoxycarbonyl; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluroniumHexafluorophosphate; HCl for hydrogen chloride; HOBT for1-hydroxybenzotriazole; K₂CO₃ for potassium carbonate; n-BuLi forn-butyl lithium; i-BuLi for i-butyl lithium; t-BuLi for t-butyl lithium;PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP forlithium 2,2,6,6-tetramethylpiperidinate; MeOH for methanol; Mg formagnesium; MOM for methoxymethyl; Ms for mesyl or —SO₂—CH₃; Ms₂O formethanesulfonic anhydride or mesyl-anhydride; NaBH₄ for sodiumborohydride; NaBH₃CN for sodium cyanoborohydride; NaN(TMS)₂ for sodiumbis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodiumhydride; NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;Na₂CO₃ sodium carbonate; NaOH for sodium hydroxide; Na₂SO₄ for sodiumsulfate; NaHSO₃ for sodium bisulfite or sodium hydrogen sulfite; Na₂S₂O₃for sodium thiosulfate; NH₂NH₂ for hydrazine; NH₄HCO₃ for ammoniumbicarbonate; NH₄Cl for ammonium chloride; NMMO for N-methylmorpholineN-oxide; NaIO₄ for sodium periodate; Ni for nickel; OH for hydroxyl;OsO₄ for osmium tetroxide; Pd for palladium; Ph for phenyl; PMB forp-methoxybenzyl; POPd for dihydrogendichlorobis(di-tert-butylphosphinito-κP)palladate(II); Pd₂(dba)₃ fortris(dibenzylidene-acetone) dipalladium (0); Pd(PPh₃)₄ fortetrakis(triphenylphosphine)palladium (0); PdCl₂(PPh₃)₂ fortrans-dichlorobis(triphenyl-phosphine)palladium (II); Pt for platinum;Rh for rhodium; rt for room temperature; Ru for ruthenium; SEM for(trimethylsilyl)ethoxymethyl; TBAF for tetrabutylammonium fluoride; TBSfor tent-butyl dimethylsilyl; TEA or Et₃N for triethylamine; Teoc for2-trimethylsilyl-ethoxy-carbonyl; TFA for trifluoroacetic acid; THF fortetrahydrofuran; TMEDA for N,N,N′,N′-tetramethylethylenediamine; TPP orPPh₃ for triphenyl-phosphine; Troc for 2,2,2-trichloroethyl carbonyl; Tsfor tosyl or —SO₂—C₆H₄—CH₃; Ts₂O for tolylsulfonic anhydride ortosyl-anhydride; TsOH for p-tolylsulfonic acid; TMS for trimethylsilyl;or TMSCl for trimethylsilyl chloride.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared. Starting materials can be obtained from commercial sources orprepared by well-established literature methods known to those ofordinary skill in the art. It will be readily apparent to one ofordinary skill in the art that the compounds defined above can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. It will also be readily apparent to oneskilled in the art that the selective protection and deprotection steps,as well as the order of the steps themselves, can be carried out invarying order, depending on the nature of the variables to successfullycomplete the syntheses below. The variables are as defined above unlessotherwise noted below.

The compounds of the present invention may be prepared via severaldifferent synthetic routes from a variety of 5/6-membered ring fusedheteroaryl, 5-membered ring heteroaryl, and related intermediates. Anexemplary method is shown in Schemes 1, 2, 3, and 4. A retro-synthesisof those title compounds include direct formation of a suitably linkedcore structure (5/6-membered ring fused heteroaryl or 5-membered ringheteroaryl) followed by attachment of a suitable capping group (such as—C(O)R⁶), plus some functional group manipulations in between and/orafter. Various 5/6-membered ring fused heteroaryl or 5-membered ringheteroaryl intermediates are known to those skilled in the art, forexample see the encyclopedic volumes edited by A. R. Katrizky, et al,“Comprehensive Heterocyclic Chemistry” 1984; “Comprehensive HeterocyclicChemistry II” 1996; “Comprehensive Heterocyclic Chemistry III” 2008.

A general synthesis and further elaboration of some 6-membered ringfused with imidazole related intermediates are summarized in Scheme 1,in which Z is N or CH.

The synthesis starts from the construction of an optionally substitutedimidazopyridine or benzimidazole 1-2, which may be obtained bycondensation of an amino acid or its derivatives 1-1.1 or 1-1.2 with2,3-diaminopyridine or 1,2-diaminobenzene 1-1 under the conditions tothose skilled in the art. The imidazole ring closure may be realizedeither in one pot by heat, optionally in the presence of an acid and/orwith a dehydration reagent such as polyphosphoric acid; or in twosteps: 1) amide formation between diamine 1-1 and amino acid 1-1.1 or1-1.2 in the presence of a condensation reagent such as EDC.HCl, DCC orthe like; or through mixed anhydride approach by reacting acid 1-1.1 or1-1.2 with a chloroformate such as methyl chloroformate, isobutylchloroformate, or the like, in the presence of a base such as TEA,DIPEA, DMAP, N-methylmorpholine, or the like, followed by treating themixed anhydride with diamine 1-1; and 2) the heterocyclic ring closurein the presence of an acid such as acetic acid, sulfuric acid or thelike or a dehydration reagent such as HATU or the like, optionally withheat.

The imidazopyridine or benzimidazole 1-2 may be subjected to Suzuki,Stille or related coupling conditions known to those skilled in the art(see reviews: A. Suzuki, Pure Applied Chem. 1991, 63, 419; A. Suzuki,Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1,249; A. Anastasia, et al, Handbook of Organopalladium Chemistry forOrganic Synthesis 2002, 1, 311; F. Bellina, et al, Synthesis 2004, 2419;M. G. Organ, et al, Synthesis 2008, 2776; A. T. Lindhardt, et al,Chem.—A European J. 2008, 14, 8756; E. A. B. Kantchev, et al, Angew.Chem. Int. Ed. 2007, 46, 2768; V. Farina, et al, Advances inMetal-Organic Chem. 1996, 5, 1) with different coupling partners toprovide a variety of key intermediates. For example, Sonogashiracoupling between bromide 1-2 and trimethylsilylacetylene can generatealkyne 1-3 after removal of TMS by K₂CO₃ in MeOH. Alternatively, bromide1-2 may be coupled with tributylvinylstanne through Stille reactionconditions known to those skilled in the art to provide alkene 1-4.Analogously, a key allyl intermediates 1-5 may be prepared by Stillereaction from bromide 1-2 with an allylstanne such asallyltributylstanne.

Alternatively, bromide 1-2 may be converted to key intermediate 1-7 byselectively reacting with metallic reagent 1-2.2 under the Suzuki orStille conditions which are known to those skilled in the art. Yetalternatively, intermediate 1-7 may be prepared by treating bromide 1-2with dimetallic agent 1-2.1 to afford organometallic 1-6, followed bycoupling with bromoiodoaryl compound 1-6.1, both may be under thepreviously described Suzuki or Stille reaction conditions. The bromide1-7 may be further converted to organometallic 1-8 with dimetallic agent1-2.1 using the conditions described above to prepare 1-6.

It should be noted that optionally the NH group of all theimidazopyridine or benzimidazole related intermediates listed above maybe protected with an amino protecting group, such as SEM (i.e. SEM-Cl,NaH), Boc, Cbz, Teoc, Troc, or the like.

A typical synthesis of imidazole related intermediates are analogous tothat of the imidazopyridine or benzimidazole intermediates. As shown inScheme 2, bromo-imidazole 2-2 can be synthesized by condensation ofamino acid derived aldehyde 2-1.1 or 2-1.2 and glyoxal in the presenceof methanolic ammonia; followed by bromination of the imidazole ringunder the conditions which are known to those skilled in the art. Thebromination of the imidazole ring may be realized either in one pot byNBS, bromine, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, or the like; orin two steps: 1) dibromide formation in the presence of excessbromination reagent such as NBS, bromine,2,4,4,6-tetrabromo-2,5-cyclohexadienone, or the like, optionally withheat; and 2) reduction of the dibromide to monobromide in the presenceof a reducing reagent such as NaHSO₃, Na₂S₂O₃, Na₂SO₃, or the like.Bromide 2-2 then may be served as a common intermediate furtherelaborable to many other imidazole derivatives using the chemistrydiscussed in Scheme 1. For example, bromide 2-2 may be coupled withallytin or vinyltin or TMS-acetylene to provide intermediate 2-6. Also,bromide 2-2 may be converted to key intermediate 2-4 by selectivelyreacting with metallic reagent 2-2.1 under the Suzuki or Stilleconditions to provide key intermediate 2-4. Yet alternatively,intermediate 2-4 may be prepared by treating bromide 2-2 with dimetallicagent 2-2.2 to afford organometallic 2-5, followed by coupling withbromoiodoaryl compound 2-5.1, both may be under the previously describedSuzuki or Stille reaction conditions. In turn, the bromide 2-4 may befurther converted to organometallic 2-7 with dimetallic agent 2-4.1using the conditions described above for the preparation of intermediate2-5.

Yet alternatively, aryl or heteroaryl bromide 2-4 may also be derivedfrom bromoketone 2-9, which can be prepared from the correspondingketone 2-8 in the presence of a bromination reagent such as NBS,bromine, or the like, optionally in the presence of an acid and/or withheating. Bromoketone 2-9 may be either converted to the correspondingamine 2-11, or coupled with protected amino acid 1-1.1 or 1-1.2 in thepresence of a base such as Et₃N or DIPEA to afford keto-ester 2-10.Similarly, amine 2-11 may be converted to the corresponding keto-amide2-12 via condensation with appropriate amino acid under standard amideformation conditions. Both 2-12 and 2-13 may be transformed to keyintermediate 2-4 via heating with NH₄OAc under thermal or microwaveconditions.

As shown in Scheme 3, a compound 3-1 containing a hydroxy groupsubstituted at the C4-position of the pyrrolidine ring may beillustrated by intermediates 1-2, 1-3, 1-4, 1-5, 1-7, 2-2, 2-4, and 2-6when U is CH(OH) as shown in Schemes 1-2. Oxidation of 3-1 by a varietyof oxidation agents such as Dess-Martin periodinane optionally in thepresence of an acid such as acetic acid or camphorsulfonic acid toafford the ketone 3-2. More reagents and conditions for the oxidation ofan alcohol to a ketone can be found in Comprehensive Organictransformations R. C. Larock Ed., Wiley-RCH, 1999, page 1236-1249. 3-2may then serve as a universal intermediate for further derivatization toolefin 3-3, oxime 3-4 and hydrazone 3-5. The olefination of 3-2 may berealized by various types of Wittig Reaction or Peterson Reaction, amore detailed reagents and conditions can be found in ComprehensiveOrganic transformations R. C. Larock Ed., Wiley-RCH, 1999, page 327-350.

With a variety of suitably substituted imidazopyridines, benzimidazolesand imidazoles such as those listed in Schemes 1-3 in hand, thecompounds of the present invention may be prepared through variouscoupling strategy or a combination of strategies to connect twofragments, optionally with a suitable cyclic or acyclic linker orformation of a cyclic or acyclic linker. The said strategy may include,but not limited to, Stille coupling, Suzuki coupling, Sonogashiracoupling, Heck coupling, Buchwald amidation, Buchwald amination, amidecoupling, ester bond formation, William etherification, Buchwaldetherification, alkylation, pericyclic reaction with differentvariations, or the like.

An example of the strategies that may be used to prepare the compoundsof the present invention is shown in Scheme 4. Both iodide 4-1.1 andalkyne 4-1.2 can be prepared using similar procedures described inSchemes 1-3. Iodide 4-1.1 can be coupled with benzimidazolylacetylene4-1.2 under Sonogashira condition in the presence of Pd and Cu-catalyststo generate a core structure 4-2. Compound 4-2 then may be served as acommon intermediate for further derivatizations to the title compoundsI-1 in two steps: 1) deprotection of Boc groups under hydrolyticconditions in the presence of an acid such as TFA or hydrogen chloride;and 2) the released amine functionality may be acylated with acarboxylic acid under standard acylation conditions, for example acoupling reagent such as HATU in combination with an organic base suchas DIPEA can be used in this regard. Various carboxylic acids includingamino acids in racemic or optical form are commercially available,and/or can be synthesized in racemic or optical form, see referencescited in reviews by D. Seebach, et al, Synthesis 2009, 1; C. Cativielaand M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry 2007, 18, 569; 2000,11, 645; and 1998, 9, 3517; and experimental examples compiled in patentapplication WO 08/021,927A2 by C. Bachand, et al, from BMS, which isincorporated herein by reference.

Alternatively, as shown in Scheme 4a, the compounds of the presentinvention (for example I-1) may also be derived from key intermediates4-1.1a and 4-1.2a using the Sonogashira coupling procedures describedpreviously. The intermediates 4-1.1a and 4-1.2a have the desired acylgroups already installed from 4-1.1 and 4-1.2 using similar sequencesshown in Scheme 4.

Yet alternatively, as shown in Scheme 4b, the compounds of the presentinvention (for example I-1) may also be derived from key intermediate4-2b after Sonogashira coupling of 4-1.1 and 4-1.2b using the proceduresdescribed previously. The alcohol in 4-2b may be oxidized and olefinatedto exocyclic double bond compound 4-3b using the procedures described inScheme 3. 4-3b can then be further converted to I-1 using similarsequences shown in Scheme 4.

The compounds of the present invention containing five-memberedheteroaryl other than imidazole may be prepared using similar proceduresdescribed above in Schemes 1-4 and 4a. For example, some intermediatescontaining a desired, suitably substituted five-membered heteroaryl havebeen published in US 2008/0311075A1 by C. Bachand, et al from BMS, whichis incorporated by reference. These intermediates are compiled in thefollowing Table 11.

TABLE 11

The synthesis of the compounds of the present invention involves5/6-membered fused heteroaryl intermediates other than benzimidazoles,various 5/6-membered fused heteroaryl are known in the literature. Thesynthesis of other 5/6-membered fused heteroaryl intermediates dependson the chemical features of each structure. For example, a typicalsynthesis of indole intermediate is illustrated in Scheme 5. Thecommercially available bromoiodoaniline 5-1 may be coupled to thecommercially available acetylene 5-1.1 under the Sonogashira conditionsto give phenylacetylene 5-2. The latter may be cyclized to indole 5-3under heat or microwave condition in the presence of a copper catalyst.

It will be appreciated that, with appropriate manipulation andprotection of any chemical functionality, synthesis of compounds ofFormula (I) is accomplished by methods analogous to those above and tothose described in the Experimental section. Suitable protecting groupscan be found, but are not restricted to, those found in T W Greene and PG M Wuts “Protective Groups in Organic Synthesis”, 3rd Ed (1999), JWiley and Sons.

In certain aspects, the invention is directed to a method of preparing acompound of Formula (I) comprising the steps of:

-   -   i) preparing a compound of Formula (II):

via a transition-metal catalyzed cross-coupling reaction;

wherein:

G, J, U, X, R¹, R³, R⁴, R⁵, R^(7a) and R^(7b) are as previously definedin Formula (I);

Ring A¹ is absent, optionally substituted aryl or optionally substitutedheteroaryl;

Ring B¹ is optionally substituted aryl or optionally substitutedheteroaryl;

L¹ is absent, optionally substituted C₂-C₄ alkenyl or C₂-C₄ alkynyl; and

Z^(a) and Z^(b) are each independently an amino protecting group or—C(O)—R⁶;

-   -   ii) when Z^(a) or Z^(b) is an amino protecting group, fully or        selectively deprotecting a compound of Formula (II) to give the        corresponding amine of Formula (III):

wherein Z′ is hydrogen, an amino protecting group or —C(O)—R⁶;

-   -   iii) capping the released amino group of a compound of        Formula (III) with LG-C(O)—R⁶, wherein LG is a leaving group; to        give the compound of Formula (IV):

wherein Z^(d) is an amino protecting group —C(O)—R⁶; and

-   -   iv) repeated reaction sequence of deprotecting and capping (step        ii-iii) to give the compound of Formula (V):

All references cited herein, whether in print, electronic, computerreadable storage media or other form, are expressly incorporated byreference in their entirety, including but not limited to, abstracts,articles, journals, publications, texts, treatises, internet web sites,databases, patents, and patent publications.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Although the invention has been described with respect to variouspreferred embodiments, it is not intended to be limited thereto, butrather those skilled in the art will recognize that variations andmodifications may be made therein which are within the spirit of theinvention and the scope of the appended claims.

Example 1

Step 1a. Into a mixture of 2-bromo-1-(4-iodophenyl)ethanone (5.00 g,15.4 mmol) and N-Boc-L-proline (3.48 g, 16.1 mmol) in acetonitrile (40mL) was added diisopropylethylamine (2.4 mL, 17 mmol). The resultingmixture was stirred at rt for 3 hours before being partitioned betweenEtOAc and aqueous NaHCO₃. The organic phase was separated, dried(Na₂SO₄) and concentrated to afford a brown oil. It was purified byflash column chromatography (silica, hexane-EtOAc) to give the desiredproduct as a light yellow oil (6.00 g, 86%). ESIMS m/z=481.94 [M+Na]⁺.Step 1b. The mixture of compound from step 1a (6.00 g, 12.5 mmol) andammonium acetate (15.1 g, 196 mmol) in toluene (80 mL) was stirred at80° C. for 3 hours before being partitioned between EtOAc and aqueousNaHCO₃. The organic phase was separated, dried (Na₂SO₄) and concentratedto afford a deep red oil. It was purified by flash column chromatography(silica, hexane-EtOAc) to give the desired product as a light yellowsolid (5.34 g, 93%). ESIMS m/z=439.83 [M+H]⁺.Step 1c. A mixture of N-Boc-L-4-hydroxyproline (6.182 g, 26.73 mmol) and4-bromo-1,2-diaminobenzene (5.000 g, 26.73 mmol) in DMF (60 mL) wastreated with EDC.HCl (6.662 g, 34.75 mmol) and DMAP (0.327 g, 2.673mmol) at rt. The mixture was stirred at rt overnight before beingpartitioned (EtOAc—H₂O). The organic layer was extracted withdichloromethane. The combined organic layers were washed with brine(*3), dried (Na₂SO₄), filtered and evaporated to give the crude desiredcompound as a dark liquid (14.05 g), which was used directly for nextstep.Step 1d. A solution of the crude compound from step 1c (14.05 g, 26.73mmol at most) in glacial acetic acid (50 mL) was heated at 50° C. for 2hours. The volatiles were evaporated off. Et₃N (5 mL) was added and themixture was evaporated again. The residue was purified by chromatography(silica, hexanes-ethyl acetate, with 10% MeOH and 1% Et₃N in ethylacetate) to give the desired compound as a brown solid (7.29 g, 71% over2 steps). ESIMS m/z=382.06, 384.06 [M+H]⁺.Step 1e. A mixture of the compound from step 1d (0.500 g, 1.308 mmol),trimethylsilyl-acetylene (1.85 ml, 13.08 mmol), CuI (7.5 mg, 0.039 mmol)and Pd(PPh₃)₄ (75.6 mg, 0.065 mmol) in Et₃N (13 mL) and THF (6 mL) wasdegased and then heated at 90° C. under N₂ overnight before beingevaporated. The residue was purified by chromatography (silica,hexanes-ethyl acetate, with 10% MeOH and 1% Et₃N in ethyl acetate) togive the desired compound as a yellow solid (0.400 g, 79%). ESIMSm/z=400.21 [M+H]⁺.Step 1f. A suspension of the compound from step 1e (0.400 g, 1.002 mmol)and K₂CO₃ (0.346 g, 2.504 mmol) in methanol (10 mL) was stirred at rtfor 2 hour. The volatiles were evaporated off. The residue waspartitioned (EtOAc—H₂O). The organic layer was washed with brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified bychromatography (silica, hexanes-ethyl acetate, with 10% MeOH and 1% Et₃Nin ethyl acetate) to give the desired compound as a yellow foam (0.237g, 72%). ESIMS m/z=328.09 [M+H]⁺.Step 1g. To a mixture of the compounds from step 1b (0.122 g, 0.278mmol) and step 1f (0.100 g, 0.305 mmol) in THF (4.5 mL) andtriethylamine (1.5 mL) was addedtetrakis(triphenylphosphine)palladium(0) (16.0 mg, 0.014 mmol) andcopper(I) iodide (1.6 mg, 8.3 μmol). The resulting mixture was degassedand then stirred at room temperature for 1 hours, at 35° C. for 15 hoursand at 55° C. for 3 hours before being evaporated. The residue waspurified by flash column chromatography (silica, hexanes-ethyl acetate,with 20% MeOH and 1% Et₃N in ethyl acetate) to give the desired compoundas a yellow solid (0.102 g, 57%). ESIMS m/z=639.36 [M+H]⁺.Step 1h. To a solution of the compound from step 1g (40.0 mg, 62.6 μmol)in CH₂Cl₂ (4 mL) were added camphorsulfonic acid (29.1 mg, 0.125 mmol)and Dess-Martin periodinane (0.265 g, 0.626 mmol). The mixture wasstirred at rt for 3 hours before being quenched with aqueous Na₂S₂O₃solution. The volatiles were evaporated and the residue was partitioned(EtOAc—H₂O). The organics were washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flash columnchromatography (silica, CH₂Cl₂-MeOH) to give the desired compound as ayellow solid (36.5 mg, 92%). ESIMS m/z=637.62 [M+H]⁺.Step 1i. To a suspension of PPh₃MeBr (0.315 g, 0.882 mmol) in THF (8 mL)was added t-BuOK (1M in THF, 0.80 mL, 0.802 mmol) at rt. The mixture wasstirred at rt for 1 hour before a solution of the compound from step 1h(0.102 g, 0.160 mmol) in THF (6 mL) was added. The resultant mixture wasallowed to react for 6 hours before being evaporated to dryness. Theresidue was partitioned (EtOAc—H₂O) and the organics were washed withbrine, dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash column chromatography (silica, hexanes-ethyl acetate) to givethe title compound as a light yellow solid (90.0 mg, 88%). ESIMSm/z=635.42 [M+H]⁺.

Example 83

Step 83a. A solution of the compound from example 1 (90.0 mg, 0.142mmol) in CH₂Cl₂ (4 mL) was treated with HCl in 1,4-dioxane (4 M, 3 mL)for 10 min. The volatiles were evaporated off to give the crude desiredcompound as a yellow solid which was directly used in the next step.ESIMS m/z=435.37 [M+H]⁺.Step 83b. A mixture of the crude compound from step 83a (0.142 mmol atmost) and (S)-(methoxycarbonyl)amino-3-methyl-butyric acid (preparedaccording to WO 2008/021927, 52.1 mg, 0.298 mmol) in DMF (3 mL) wastreated with HATU (0.108 g, 0.284 mmol) in the presence of DIPEA (0.35mL, 2.84 mmol) for 1 hour at rt. The volatiles were evaporated off toprovide a brown syrup, which was purified by flash column chromatography(silica, CH₂Cl₂-MeOH) to give the title compound as a light yellow solid(79.2 mg, 2 steps 75%). ESIMS m/z=749.59 [M+H]⁺.

Example 252

The title compound was prepared from the compound of Example 332 usingprocedures similar to that described in example 83. ESIMS m/z=751.46[M+H]⁺.

Example 300

The title compound was prepared from the compound of example 317 usingprocedures similar to that described in example 83. ESIMS m/z=749.41[M+H]⁺.

The title compounds of examples 2-82, 84-251, 253-299, 301-315 can beprepared using the chemistry described in the Synthetic Methods and/orExamples 1, 83, 252, 300 and 316-337.

TABLE 1 Examples 1-219

Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

TABLE 2 Example 220-229

Entry R R′ R″ U Entry R R′ R″ U 220 Me H H CH₂ 221 H H H CF₂ 222 Me H HS 223 H H H

224 H Me H CH₂ 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

TABLE 3 Examples 230-239

Entry R R′ R″ Entry R R′ R″ 230 Me H H 231 H CO₂Me H 232 H F H 233 H HCO₂Me 234 H H F 235 H OMe H 236 H Cl H 237 H H OMe 238 H H Cl 239 H CF₃H

TABLE 4 Examples 240-249

Entry R R′ R″ R′′′ Entry R R′ R″ R′′′ 240 F H H H 241 F F H H 242 Me H HH 243 Me Me H H 244 H H Me Me 245 H H Et Et 246 CF₃ H H H 247 CF₃ H CF₃H 248 Cl H H H 249 Cl H Cl H

TABLE 5 Examples 250-264

Entry R Entry R 250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

TABLE 6 Examples 265-282

Entry A^(a) Entry A^(a) 265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

TABLE 7 Example 283-303

Entry A^(a) Entry A^(a) 283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

TABLE 8 Examples 304-315

Entry G^(g) Entry G^(g) Entry G^(g) 304

305

306

307

308

309

310

311

312

313

314

315

Example 316

Step 316a. A solution of the compound from step 1g of example 1 (50.0mg, 78.3 μmol) in 1,4-dioxane (1 mL) was treated with HCl in 1,4-dioxane(4 M, 4 mL) at rt for 2 hours. The volatiles were evaporated off to givethe crude desired compound as a yellow solid which was directly used inthe next step.Step 316b. A mixture of the crude compound from step 316a (78.3 μmol atmost) and (S)-(methoxycarbonyl)amino-3-methyl-butyric acid (preparedaccording to WO 2008/021927, 27.4 mg, 0.157 mmol) in DMF (3 mL) andDIPEA (0.27 mL, 1.566 mmol) was treated with HATU (56.5 mg, 0.149 mmol)for 1 hour at rt. The volatiles were evaporated off to provide a brownsyrup, which was purified by flash column chromatography (silica,silica, hexanes-ethyl acetate, with 25% MeOH and 1% Et₃N in ethylacetate) to give the desired compound as a yellow solid (52.7 mg, 89%over 2 steps). ESIMS m/z=753.46 [M+H]⁺.Step 316c. To a solution of the compound from step 316b (38.6 mg, 51.3μmol) in CH₂Cl₂ (3 mL) were added camphorsulfonic acid (23.8 mg, 0.103mmol) and Dess-Martin periodinane (0.131 g, 0.308 mmol). The mixture wasstirred at rt for 2 hours before another addition of Dess-Martinperiodinane (0.131 g, 0.308 mmol). The resultant mixture was allowed toreact for another 3 hours before being quenched with aqueous Na₂S₂O₃solution. The volatiles were evaporated and the residue was partitioned(EtOAc—H₂O). The organics were washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flash columnchromatography (silica, CH₂Cl₂-MeOH) to give the desired compound as ayellow brown solid (33.2 mg, 86%). ESIMS m/z=751.54 [M+H]Step 316d. To a solution of the compound from step 316c (4.0 mg, 5.3μmol) in 1,4-dioxane (2 mL) was added MeONH₂.HCl (4.4 mg, 53.0 μmol).The mixture was stirred for 14 hours before being evaporated to dryness.The residue was purified by flash column chromatography (silica,CH₂Cl₂-MeOH) to give the title compound as a white solid (2.7 mg, 66%).ESIMS m/z=780.49 [M+H]⁺.

Example 317

The title compound was prepared using procedures similar to thatdescribed in example 1. ESIMS m/z=635.30 [M+H]⁺.

Example 318

Step 318a. To a suspension of activated zinc powder (2.40 g, 36.7 mmol)in dry THF (50 mL) was added allyl bromide (3.1 mL, 36.7 mmol) dropwise.The resulting light yellow solution was cooled to −30° C. before the(S)-1-tert-butyl-2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (4.16 g,17.1 mmol) was added dropwise. The reaction mixture was stirred at <−10°C. for 4 hours before being quenched with HCl (1 N). The mixture waspartitioned (EtOAc—H₂O). The organics were washed with brine, dried(Na₂SO₄) and evaporated. The residue was purified by flash columnchromatography (silica, EtOAc-hexanes) to afford the desired compound asa light yellow oil (4.85 g, 98%). ESIMS m/z=286.15 [M+H]⁺.Step 318b. To a solution of the compound from step 318a (0.200 g, 0.627mmol) in CH₃CN (4 mL) were added NaHCO₃ (0.211 g, 2.51 mmol) and iodine(0.477 g, 1.88 mmol). The resultant mixture were heated up to 50° C. for4 hours before the second addition of NaHCO₃ (0.211 g, 2.51 mmol) andiodine (0.477 g, 1.88 mmol). The reaction was kept at 50° C. for another3 hours before being cooled down and quenched by aqueous Na₂S₂O₃. Thevolatiles were evaporated and the residue was partitioned (EtOAc—H₂O).The organics were washed with brine, dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash column chromatography(silica, EtOAc-hexanes) to give the desired compound as a colorless oil(79.8 mg, 29%). ESIMS m/z=468.23 [M+Na]⁺.Step 318c. Into a solution of the compound from step 318b (1.18 g, 2.66mmol) in toluene (50 mL) were added tris(trimethylsilyl)silane (2.05 mL,6.66 mmol) and 2,2′-azo-bis-isobutyronitrile (26.2 mg, 0.160 mmol). Theresultant mixture were degassed and heated up to 90° C. under N₂ for 3hours before being allowed to cool down and evaporated to dryness. Theresidue was purified by flash column chromatography (silica,EtOAc-hexanes) to give the desired compound as a colorless oil (0.333 g,39%). ESIMS m/z=320.16 [M+H]⁺.Step 318d. Into a solution of the compound from step 318c (0.170 g,0.533 mmol) in MeOH (6 mL) were added palladium hydroxide (20 wt % oncarbon, 50.0 mg) and Boc₂O (0.174 g, 0.799 mmol). The resulting mixturewas hydrogenated under 60 psi hydrogen gas at room temperature for 1 daybefore being filtered through a plug of celite. The filtrate wasconcentrated and purified by flash column chromatography (silica,EtOAc-hexanes) to give the desired compound as a colorless oil (0.127 g,84%). ESIMS m/z=308.14 [M+Na]⁺.Step 318f. Into a solution of the compound from step 318d (0.127 g,0.447 mmol) in EtOH (4 mL) at 0° C. was added lithium hydroxidemonohydrate (22.5 mg, 0.536 mmol) in H₂O (2 mL). The resulting mixturewas gradually warmed up to room temperature for 1 day before beingevaporated to dryness. The residue was partitioned (Et₂O—H₂O) and theaqueous phase was acidified to pH ˜2 at 0° C. The mixture was thenpartitioned (CH₂Cl₂—H₂O) and the organics were washed with brine, dried(Na₂SO₄), filtered and evaporated to give the crude desired compound asa colorless oil (0.122 g, 100%). ESIMS m/z=319.14 [M+Li+CH₃CN]⁺.Step 318g. Into a mixture of the crude compound from step 318f (60.5 mg,0.223 mmol at most) and 4-bromo-1,2-diaminobenzene (46.0 mg, 0.246 mmol)in CH₃CN (4 mL) were added EDC.HCl (55.7 mg, 0.291 mmol) and DMAP (5.5mg, 44.7 μmol). The mixture was stirred at room temperature for 14 hoursbefore being evaporated to dryness. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give thedesired compound as a yellow, brown oil (82.0 mg, 83%). ESIMSm/z=440.11, 442.11 [M+H]⁺.Step 318h. A solution of the compound from step 318g (82.0 mg, 0.186mmol) in AcOH (8 mL) was heated at 50° C. for 16 hours before beingevaporated to dryness. The residue was was partitioned (EtOAc—H₂O) andthe organics were dried (Na₂SO₄), filtered and evaporated. The residuewas purified by flash column chromatography (silica, hexanes-ethylacetate) to give the desired compound as a yellow oil (54.5 mg, 69%).ESIMS m/z=422.11, 424.14 [M+H]⁺.Step 318i. A mixture of the compound from step 318h (1.88 g, 4.47 mmol)and ethynyltrimethylsilane (6.32 mL, 44.7 mmol) in Et₃N (45 mL) wereadded CuI (25.5 mg, 0.134 mmol) and Pd(PPh₃)₄ (0.258 g, 0.223 mmol). Theresultant mixture were degassed and heated to 95° C. under N₂ for 20hour. The volatiles were evaporated and the residue was partitioned(EtOAc—H₂O). The organics were washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flash columnchromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a light yellow brown foam (1.79 g, 91%). ESIMS m/z=440.27[M+H]⁺.Step 318j. A solution of the compound from step 318i (1.79 g, 4.08 mmol)in MeOH (40 mL) was treated with K₂CO₃ (1.41 g, 10.2 mmol) for 2 hoursbefore being evaporated to dryness. The residue was partitioned(EtOAc—H₂O) and the organics were dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as a lightyellow solid (1.35 g, 90%). ESIMS m/z=368.23 [M+H]⁺.Step 318k. Into a solution of(S)-1-(tert-butoxycarbonyl)-4-methylenepyrrolidine-2-carboxylic acid(2.02 g, 9.06 mmol) in acetonitrile (12 mL) and DIPEA (6 mL) was addedthe 2-bromo-1-(4′-iodophenyl)ethanone (3.1 g, 9.5 mmol). The resultingsolution was stirred at room temperature overnight (16 h) before wasconcentrated to give a brownish oil. This crude product was purified byflash column chromatography (silica, EtOAc-hexanes) to afford thedesired compound as a light yellow oil (4.37 g, 98%).Step 318l. Into a solution of the compound from step 318k (4.37 g, 9.27mmol) in toluene (60 mL) was added ammonium acetate (7.9 g, 102 mmol).The resulting mixture was heated at 107° C. for 12 h before being cooledand partitioned (H₂O-EtOAc). The organic phase was separated, dried(Na₂SO₄) and concentrated to afford a brown oil, which was purified byflash column chromatography (silica, EtOAc-hexanes) to afford thedesired compound as a yellow foam (3.3 g, 80%). ESIMS m/z=452.01[M+H]⁺.Step 318m. A mixture of compounds from step 318j (45.0 mg, 0.122 mmol),compounds from step 318l (55.3 mg, 0.122 mmol),tetrakis(triphenylphosphine)palladium(0) (7.1 mg, 6.1 μmol) andcopper(I) iodide (0.7 mg, 3.7 μmol) in triethylamine (2 mL) andacetonitrile (2 mL) was degassed and heated at 40° C. for 15 hours underN₂. The mixture was evaporated. The residue was purified by flash columnchromatography (silica, hexanes-EtOAc, with 1% Et₃N in EtOAc) to givethe title compound as a yellow solid (82.0 mg, 97%). ESIMS m/z=691.45[M+H]⁺.

Example 319

The title compound was prepared from the compound of example 318 usingprocedures similar to that described in example 83. ESIMS m/z=805.45[M+H]⁺.

Example 320

Step 320a. To a solution of LiHMDS (1.0 M in THF, 5.17 mL, 5.17 mmol) inTHF (20 mL) at −78° C. was added a solution of(+)-(3R,7aS)-tetrahydro-3-phenyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one (0.500g, 2.460 mmol) in THF (10 mL) under N₂. The mixture was stirred at −78°C. for 30 min before ClCO₂Me (0.19 mL, 2.460 mmol) was added at −78° C.After 30 min at −78° C., the reaction was quenched with saturated NH₄Clsolution. The mixture was allowed to warm up to rt and the volatileswere evaporated. The residue was partitioned (EtOAc—H₂O). The organicswere washed with brine, dried (Na₂SO₄), filtered and evaporated. Theresidue was purified by flash column chromatography (silica,EtOAc-hexanes) to give the desired compound as a colorless oil (0.598 g,93%). ESIMS m/z=262.13 [M+H]⁺.Step 320b. To a solution of the compound from step 320a (0.350 g, 1.340mmol) in THF (13 mL) at 0° C. was added NaH (60% in mineral oil, 64.3mg, 1.607 mmol). After addition, the mixture was stirred at rt for 15min before allyl bromide (0.13 mL, 1.474 mmol) was added. After 1 h atrt, the reaction was quenched with saturated NH₄Cl solution. The mixturewas partitioned (EtOAc—H₂O). The organics were washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashcolumn chromatography (silica, EtOAc-hexanes) to give the desiredcompounds as two separated diastereomers: minor diastereomer (lesspolar, 56.0 mg, 14%), (3R,6R,7aS)-methyl6-allyl-5-oxo-3-phenylhexahydropyrrolo[1,2-c]oxazole-6-carboxylate,ESIMS m/z=302.19 [M+H]⁺, ¹H NMR (CDCl₃) 7.44-7.33 (m, 5H), 6.32 (s, 1H),5.75-5.66 (m, 1H), 5.19-5.18 (m, 1H), 5.16 (s, 1H), 4.28-4.22 (m, 2H),3.78 (s, 3H), 3.57-3.52 (m, 1H), 2.90 (dd, J=6.7, 13.4 Hz, 1H), 2.85(dd, J=7.9, 14.1 Hz, 1H), 2.58 (dd, J=6.7, 14.1 Hz, 1H), 1.89 (dd,J=6.6, 13.2 Hz, 1H); major diastereomer (more polar, 0.222 g, 55%),(3R,6S,7aS)-methyl6-allyl-5-oxo-3-phenylhexahydropyrrolo[1,2-c]oxazole-6-carboxylate,ESIMS m/z=302.19 [M+H]⁺, ¹H NMR (CDCl₃) 7.46-7.33 (m, 5H), 6.33 (s, 1H),5.82-5.73 (m, 1H), 5.23-5.18 (m, 2H), 4.28 (dd, J=6.2, 6.5 Hz, 1H),4.08-4.02 (m, 1H), 3.82 (s, 3H), 3.67 (t, J=8.3 Hz, 1H), 2.80 (dd,J=7.5, 14.0 Hz, 1H), 2.71 (dd, J=7.1, 14.0 Hz, 1H), 2.54 (dd, J=4.9,12.8 Hz, 1H), 2.38 (dd, J=7.9, 13.8 Hz, 1H).Step 320c. To a solution of the major diastereomer from step 320b (0.160g, 0.585 mmol) in THF/H₂O (1/1, 6 mL) at rt was added OsO₄ (4 wt % inH₂O, 7.5 μL, 0.012 mmol), followed by NaIO₄ (0.263 g, 1.229 mmol). Theresulting mixture was stirred at rt for 2 hours before being quenchedwith saturated Na₂S₂O₃ solution. The mixture was partitioned(EtOAc—H₂O). The organics were washed with brine, dried (Na₂SO₄),filtered and evaporated to afford the desired compound as a colorlessoil (0.133 g), which was used directly for next step.Step 320d. To a solution of the compound from step 320c (0.133 g, 0.438mmol at most) in EtOH (5 mL) at 0° C. was added NaBH₄ (33.2 mg, 0.877mmol). After 20 min at 0° C., the resulting mixture was stirred at rtfor 2.5 hours. More NaBH₄ (16.6 mg, 0.438 mmol) was added. After 2 h atrt, the reaction was quenched with saturated NH₄Cl solution. Thevolatiles were evaporated. The residue was taken up in EtOAc (with 5%MeOH) and filtered. The filtrate was evaporated to dryness. The residuewas purified by flash column chromatography (silica, EtOAc-MeOH) to givethe desired compound as a white foam (67.6 mg, 46% over 2 steps). ESIMSm/z=278.17 [M+H]⁺.Step 320e. To a solution of the compound from step 320d (0.793 g, 2.860mmol) in pyridine (28 mL) at rt was added TsCl (0.600 g, 3.145 mmol).The resulting solution was stirred at rt for 40 hours. More TsCl (0.600g, 3.145 mmol) was added. After 24 hours at rt, the reaction wasquenched with saturated NaHCO₃ solution. The mixture was evaporated todryness. The residue was taken up in CH₂Cl₂ and filtered. The filtratewas directly purified by flash column chromatography (silica,EtOAc-hexanes) to give the desired compound as a colorless oil (0.511 g,69%). ESIMS m/z=260.16 [M+H]⁺.Step 320f. To a solution of the compound from step 320e (0.540 g, 2.082mmol) in THF (20 mL) at rt was added LiAlH₄ (1.0 M in Et₂O, 4.16 mL,4.16 mmol). The resulting mixture was heated at 60° C. for 2 hoursbefore being allowed to cool down. The reaction was quenched bycarefully adding H₂O (0.16 mL), followed by 15% NaOH solution (0.16 mL)and then H₂O (0.32 mL). The suspension was filtered through a short padof celite. The filtrate was evaporated to give the desired compound as awhite semi-solid (0.572 g). ESIMS m/z=248.20 [M+H]⁺.Step 320g. To a solution of the compound from step 320f (2.082 mmol atmost) in MeOH (15 mL) at rt was added HOAc (0.16 mL, 2.71 mmol),followed by Pd/C (10%, 0.100 g). The resulting mixture was stirred at rtunder H₂ (60 psi) for 2 hours before being filtered through a short padof celite. The filtrate was evaporated to give the desired compound as acolorless oil, which was used directly for next step. ESIMS m/z=158.11[M+H]⁺.Step 320h. To a solution of the compound from step 320g (2.082 mmol atmost) in 1,4-dioxane/H₂O (1/2, 21 mL) at rt was added NaHCO₃ (1.399 g,16.66 mmol), followed by (Boc)₂O (0.545 g, 2.498 mmol). The resultingmixture was stirred at rt for 15 hours. The volatiles were evaporated.The residue was partitioned (EtOAc—H₂O). The organics were washed withbrine, dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash column chromatography (silica, EtOAc-hexanes) to give thedesired compound as a colorless oil (0.252 g, 45% over 3 steps). ESIMSm/z=258.18 [M+H]⁺.Step 320i. To a biphasic mixture of the compound from step 320h (0.252g, 0.979 mmol) in CCl₄/CH₃CN/H₂O (3/4/5, 12 mL) at rt was addedRuCl₃.xH₂O (4.1 mg, 0.020 mmol), followed by NaIO₄ (0.419 g, 1.959mmol). The resulting mixture was stirred at rt for 2 hours. Thevolatiles were evaporated. The residue was taken up in EtOAc andfiltered. The filtrate was washed with brine, dried (Na₂SO₄) andfiltered. The solid from the filtration dissolved in brine and some H₂O,acidified to pH ˜2 and extracted with EtOAc. The combined organics werewashed with brine, dried (Na₂SO₄), filtered and evaporated. The residuewas purified by flash column chromatography (silica, EtOAc-MeOH) to givethe desired compound as a colorless oil (0.260 g, 98%). ESIMS m/z=272.24[M+H]⁺.Step 320j. A mixture of the compound from step 320i (0.260 g, 0.958mmol) and 4-bromo-1,2-diaminobenzene (0.197 g, 1.054 mmol) in CH₃CN (6mL) was treated with EDC.HCl (0.239 g, 1.246 mmol) and DMAP (11.7 mg,0.096 mmol) at rt. The mixture was stirred at rt for 3 hours beforebeing evaporated. The residue was purified by flash columnchromatography (silica, EtOAc-hexanes) to give the desired compound as ayellow foam (0.277 g, 64%). ESIMS m/z=440.29, 442.29 [M+H]⁺.Step 320k. A solution of the compound from step 320j (0.277 g, 0.629mmol) in glacial acetic acid (7 mL) was heated at 50° C. for 15 hours.The volatiles were evaporated off. Et₃N (5 mL) was added and the mixturewas evaporated again. The residue was purified by chromatography(silica, hexanes-ethyl acetate, with 1% Et₃N in ethyl acetate) to givethe desired compound as a yellow foam (0.247 g, 93%). ESIMS m/z=422.15,424.15 [M+H]⁺.Step 320l. A mixture of the compound from step 320k (0.247 g, 0.585mmol), trimethylsilyl-acetylene (1.24 mL, 8.772 mmol), CuI (3.3 mg,0.018 mmol) and Pd(PPh₃)₄ (33.8 mg, 0.029 mmol) in Et₃N (8 mL) wasdegased and then heated at 90° C. under N₂ overnight. Moretrimethylsilyl-acetylene (0.41 mL, 2.924 mmol) and CH₃CN (3 mL) wereadded. The mixture was heated at 90° C. for 1.5 hours before beingallowed to cool down and evaporated. The residue was purified bychromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a yellow oil (0.270 g). ESIMS m/z=440.22 [M+H]⁺.Step 320m. A suspension of the compound from step 320l (0.270 g, 0.585mmol at most) and K₂CO₃ (0.202 g, 1.462 mmol) in methanol (6 ml) wasstirred at rt for 2 hour. The volatiles were evaporated off. The residuewas taken up in CH₂Cl₂ and filtered through a short pad of celite. Thefiltrate was directly purified by chromatography (silica, hexanes-ethylacetate) to give the desired compound as a yellow foam (0.186 g, 87%over 2 steps). ESIMS m/z=368.21 [M+H]⁺.Step 320n. The title compound was prepared from the compound from step320m and compound from step 3181 using procedures similar to thatdescribed in step 318m. ESIMS m/z=691.45 [M+H]⁺.

Example 321

The title compound was prepared from the compound of example 320 usingprocedures similar to that described in example 83. ESIMS m/z=805.52[M+H]⁺.

Example 322

Step 322a. A mixture of compound from step 318l (1.100 g, 2.437 mmol),trimethylsilylacetylene (0.55 mL, 3.900 mmol), CuI (13.9 mg, 0.073 mmol)and Pd(PPh₃)₄ (0.141 g, 0.122 mmol) in Et₃N (15 mL) and CH₃CN (15 mL)was degased and then heated at 40° C. under N₂ for 40 hours before beingallowed to cool down and evaporated. The residue was purified bychromatography (silica, hexanes-ethyl acetate) to give the desiredcompound as a yellow solid (0.922 g, 90%). ESIMS m/z=422.15 [M+H]⁺.Step 322b. A suspension of the compound from step 322a (0.922 g, 2.187mmol) and K₂CO₃ (0.756 g, 5.467 mmol) in methanol (20 ml) was stirred atrt for 2 hour. The volatiles were evaporated off. The residue was takenup in CH₂Cl₂ and filtered through a short pad of celite. The filtratewas directly purified by chromatography (silica, hexanes-ethyl acetate)to give the desired compound as a light yellow foam (0.695 g, 91%).ESIMS m/z=350.17 [M+H]⁺.Step 322c. A mixture of(5S,8S)-7-(tert-butoxycarbonyl)-2-oxa-7-azaspiro[4.4]nonane-8-carboxylicacid (prepared from the minor diastereomer from step 320b following theprocedure of step 320c-320i, 0.289 g, 1.115 mmol) and1,2-diamino-4-iodobenzene (0.287 g, 1.226 mmol) in CH₃CN (10 mL) wastreated with EDC.HCl (0.278 g, 1.449 mmol) and DMAP (13.6 mg, 0.112mmol) at rt. The mixture was stirred at rt for 2.5 hours before beingevaporated. The residue was purified by flash column chromatography(silica, EtOAc-hexanes) to give the desired compound as a yellow solid(0.377 g, 69%). ESIMS m/z=488.16 [M+H]⁺.Step 322d. A solution of the compound from step 322c (0.377 g, 0.774mmol) in glacial acetic acid (8 mL) was heated at 50° C. for 15 hours.The volatiles were evaporated off. Et₃N (5 mL) was added and the mixturewas evaporated again. The residue was purified by chromatography(silica, hexanes-ethyl acetate, with 1% Et₃N in ethyl acetate) to givethe desired compound as a yellow foam (0.324 g, 89%). ESIMS m/z=470.12[M+H]⁺.Step 322e. The title compound was prepared from the compound from step322b and the compound from step 322d using procedures similar to thatdescribed in step 318m. ESIMS m/z=691.43 [M+H]⁺.

Example 323

The title compound was prepared from the compound of example 322 usingprocedures similar to that described in example 83. ESIMS m/z=805.46[M+H]⁺.

Example 324

The title compound was prepared from(S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid(prepared according to WO 2009/102325) using procedures similar to thatdescribed in step 320j-320n. ESIMS m/z=661.37 [M+H]⁺.

Example 325

The title compound was prepared from the compound of example 324 usingprocedures similar to that described in example 83. ESIMS m/z=775.40[M+H]⁺.

Example 326

Step 326a. Into a solution of the compound from step 318a (596 mmol, 2mmol, ˜8: 1 diastereomers on C-4) and allyl tent-butyl carbonate (1.26g, 8 mmol) in THF (10 mL) were added Pd₂(dba)₃ (46 mg, 0.05 mmol) andDPPB (43 mg, 0.1 mmol). The resultant mixture was degassed and thenheated at 75° C. under N₂ for 1.5 hours. After being allowed to cooldown, the solution was concentrated. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give thedesired compound as a yellow oil (605 mg, 93%). ESIMS m/z=326.26 [M+H]⁺.Step 326b. Into a solution of the compound from step 326a (677 mg, 2.08mmol) in toluene (650 mL) was added the1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(iso-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II) dichloride (76.4 mg, 0.104 mmol). The resultant mixturewas degassed and then heated at 75° C. under N₂ for 15 hours. Afterbeing allowed to cool down, the solution was concentrated. The residuewas purified by flash column chromatography (silica, hexanes-ethylacetate) to give the desired compound as a light yellow oil (585 mg,94%). ESIMS m/z=298.19 [M+H]⁺.Step 326c. Into a solution of the compound from step 326b (160 mg, 0.538mmol) in EtOH (2 mL) and H₂O (2 mL) was added LiOH.H₂O (27.1 mg, 0.646mmol). The resulting mixture was stirred at room temperature for 3 hoursbefore the volatiles were evaporated. The residue was dissolved in H₂O(10 mL) and acidified to pH 3 by adding HCl (4 N). The resulted cloudymixture was extracted with EtOAc. The organic phase was separated, dried(Na₂SO₄) and concentrated to afford the desired compound as a colorlessoil (142 mg). This oil was used directly in the next step. ESIMSm/z=284.15 [M+H]⁺.Step 326d. Into a solution of the compound from step 326c (142 mg, 0.501mmol), 4-bromo-1,2-diamine benzene (93.7 mg 0.501 mmol) and EDC.HCl (115mg, 0.6 mmol) in acetonitrile (4 mL) was added DMAP (6.1 mg, 0.05 mmol).The resulting solution was stirred at room temperature overnight (16 h).The solution was concentrated and was purified by flash columnchromatography (silica, EtOAc-hexanes) to afford the desired compound asa brownish solid (196 mg, 80% for two steps). ESIMS m/z=452.01,454.09[M+H]⁺.Step 326e. A solution of the compound from step 326d in AcOH (4 mL) washeated at 50° C. for 6 hours. After being allowed to cool down, thevolatile was evaporated. The crude oil was partitioned (aq.NaHCO₃-EtOAc). The organic phase was separated, dried (Na₂SO₄) andconcentrated to afford a brown oil, which was purified by flash columnchromatography (silica, EtOAc-hexanes) to afford the desired compound asa yellow foam (116 mg, 62%) as a single isomer. ESIMS m/z=434.13,436.13[M+H]⁺.Step 326f. Into a solution of the compound from step 326e (116 mg, 0.267mmol), trimethylsilyl acetylene (0.75 mL, 5.34 mmol) in acetonitrile (3mL) and triethylamine (2 mL) were added the Pd(PPh₃)₄ (31 mg, 0.027mmol), CuI (2.5 mg, 0.014 mmol). The resultant mixture was degassed andheated at 90° C. under N₂ for 15 hours. After being allowed to cooldown, the solution was concentrated. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give thedesired compound as an orange oil (104 mg, 78%). ESIMS m/z=452.27[M+H]⁺.Step 326g. Into a solution of the compound from step 326f (104 mg, 0.230mmol) in methanol (3 mL) was added potassium carbonate (70 mg 0.5 mmol).The resultant mixture was stirred at room temperature for 3 hours. Thevolatile was evaporated. The resulted mixture was partitioned (aq.NaHCO₃-EtOAc). The organic phase was separated, dried (Na₂SO₄) andconcentrated to afford a brown oil, which was purified by flash columnchromatography (silica, EtOAc-hexanes) to afford the desired compound asa yellow foam (76 mg, 94%). ESIMS m/z=380.20 [M+H]⁺.Step 326h. To a mixture of the compound from 326g (34.1 mg, 0.076 mmol),the compound from 3181 (23.5 mg, 0.0698 mmol) in actonitrile (2 mL) andtriethylamine (2 mL) were added Pd(PPh₃)₄ (4 mg, 0.035 mmol) and CuI (1mg). The resultant mixture was degassed and heated at 38° C. under N₂for 16 hours. The volatiles were evaporated and the residue waspartitioned (EtOAc—H₂O). The organics were washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give the titlecompound as a light yellow solid (37.3 mg, 66%). ESIMS m/z=703.25[M+H]⁺.

Example 327

The title compound was prepared from the compound of example 326 usingprocedures similar to that described in example 83. ESIMS m/z=817.32[M+H]⁺.

Example 328

Step 328a. To a solution of the minor diastereomer from step 320b (1.380g, 4.580 mmol) in THF (25 mL) at rt was added 9-BBN (0.5 M in THF, 22.90mL, 11.45 mmol). The resulting mixture was stirred at rt for 5 hoursbefore another batch of 9-BBN (0.5 M in THF, 36.64 mL, 18.32 mmol) wasadded. The solution was stirred at rt for 15 hours. H₂O (˜40 mL) wasadded, followed by NaBO₃.4H₂O (9.642 g, 59.53 mmol). The mixture wasstirred at rt for 2 hours before being partitioned (EtOAc—H₂O). Theaqueous layer was back-extracted with EtOAc. The combined organics werewashed with brine, dried (Na₂SO₄), filtered and evaporated. The residuewas purified by flash column chromatography (silica, hexanes-EtOAc) togive(3R,6S,7aS)-6-(hydroxymethyl)-6-(3-hydroxypropyl)-3-phenyltetrahydropyrrolo[1,2-c]oxazol-5(1H)-oneas a colorless oil (1.140 g, 85%). ESIMS m/z=292.15 [M+H]⁺.Step 328b. Into a solution of the compound from step 328a (957 mg. 3.28mmol), Ag₂O (1.14 g, 4.92 mmol) and NaI (110 mg. 0.63 mol) in DCM (10mL) was added a solution of TsCl (688 mg 3.61 mmol) in DCM (5 mL)dropwise. The resulting mixture was stirred for 16 hours at roomtemperature before being passed through a pad of celite. The filtratewas concentrated. The residue was purified by flash columnchromatography (silica, EtOAc-hexanes) to afford the desired compound asa yellow solid (745 mg, 51%). ESIMS m/z=446.23 [M+H]⁺.Step 328c. Into a solution of the compound from step 328b (745 mg, 1.67mmol) in THF (35 mL) was added NaH (180 mg, 4.5 mmol). The resultingmixture was heated at 30° C. for 16 hours before being allowed to cooldown and quenched with ice/water. The mixture was partitioned(EtOAc—H₂O). The organic phase was separated, dried (Na₂SO₄) andconcentrated to afford an oil, which was purified by flash columnchromatography (silica, EtOAc-hexanes) to afford the desired compound asa white solid (402 mg, 88%). ESIMS m/z=274.16 [M+H]⁺.Step 328d. Into a solution of the compound from step 328c (405 mg, 1.47mmol) in THF (5 mL) was added LiAlH₄ (1 M in THF, 3 mL, 3 mmol). Theresulting mixture was heated at 60° C. for 2 hours before being allowedto cool down. H₂O (0.1 mL), NaOH (10%, 0.15 mL) and H₂O (0.5 mL) wereadded in sequence. The resulting suspension was passed through a pad ofcelite. The filtrate was partitioned (H₂O-EtOAc). The organic phase wasseparated, dried (Na₂SO₄) and concentrated. The residue was purified byflash column chromatography (silica, EtOAc-hexanes) to afford thedesired compound as a colorless oil (337 mg, 88%). ESIMSm/z=262.16[M+H]⁺.Step 328e. Into a solution of the compound from step 328d (337 mg, 1.29mmol) in MeOH (6 mL) was added Pd/C (10%, 30 mg). The resulting mixturewas stirred under H₂ (60 psi) for 6 hours before being filtered througha pad of celite. The filtrate was concentrated to give a colorless oiland was used directly for next step. ESIMS m/z=172.13[M+H]⁺.Step 328f. Into a solution of the compound from step 328e (1.29 mmol atmost) and NaHCO₃ (650 mg, 8 mmol) in H₂O (4 mL) and dioxane (2 mL) wasadded Boc₂O (340 mg, 1.55 mmol). The resulting solution was stirred atroom temperature overnight before the volatiles were evaporated. Thecrude product was partitioned (EtOAc—H₂O). The organic phase wasseparated, dried (Na₂SO₄) and concentrated. The residue was purified byflash column chromatography (silica, EtOAc-hexanes) to afford thedesired compound as a white solid (305 mg, 87% over two steps). ESIMSm/z=272.18 [M+H]⁺.Step 328g. Into a solution of the compound from step 328f (305 mg, 1.22mmol) and RuCl₃.xH₂O (4.6 mg, 0.0225 mmol) in CCl₄ (3 mL)/ACN (4 mL)/H₂O(5 mL) was added NaIO₄ (477 mg, 2.24 mmol). The resulting mixture wasstirred at room temperature for 2 hours before being filtered through apad of celite. The filtrate was partitioned (EtOAc—H₂O). The organicphase was separated, dried (Na₂SO₄) and concentrated to afford an oil(330 mg), which was used directly in the next step. ESIMS m/z=230.11[M+H−56]⁺.Step 328h. Into a solution of the compound from step 328g (1.12 mmol atthe most), 1,2-diamine-4-iodobenzene (288 mg, 1.23 mmol) and EDC.HCl(258 mg, 1.35 mmol) in acetonitrile (6 mL) was added DMAP (14 mg, 0.112mmol). The resulting solution was stirred at room temperature overnight(16 h). The solution was concentrated. The residue was purified by flashcolumn chromatography (silica, EtOAc-hexanes) to afford the desiredcompound as a brownish foam (354 mg, 63% over two steps). ESIMSm/z=502.15 [M+H]⁺.Step 328i. A solution of the compound from step 328h in AcOH (5 mL) washeated at 55° C. for 3 hours. After being allowed to cool down, thevolatile was evaporated. The crude oil was partitioned (aq.NaHCO₃-EtOAc). The organic phase was separated, dried (Na₂SO₄) andconcentrated. The residue was purified by flash column chromatography(silica, EtOAc-hexanes) to afford the desired compound as a yellow foam(326 mg, 95%). ESIMS m/z=484.15 [M+H]⁺.Step 328j. The title compound was prepared from the compound from step328i and the compound from step 322b using procedures similar to thatdescribed in step 318m. ESIMS m/z=705.34 [M+H]⁺.

Example 329

The title compound was prepared from the compound of example 328 usingprocedures similar to that described in example 83. ESIMS m/z=819.55[M+H]⁺.

Example 330

The title compound was prepared from the major diastereomer from step320b using procedures similar to that described in example 328. ESIMSm/z=705.34 [M+H]⁺.

Example 331

The title compound was prepared from the compound of example 330 usingprocedures similar to that described in example 83. ESIMS m/z=819.55[M+H]⁺.

Example 332

Step 332a. To a mixture of 2,4′-dibromoacetophenone (5.00 g, 18.0 mmol)and N-Boc-L-proline (3.87 g, 18.0 mmol) in CH₃CN (60 mL) was addedtriethylamine (5.40 mL, 37.8 mmol) slowly. The mixture was stirred at rtuntil the disappearance of the starting material. The volatiles wereevaporated and the residue was partitioned (EtOAc-water). The organicswere washed with brine, dried (Na₂SO₄), filtered and evaporated. Theresidue was purified by flash column chromatography (silica,hexanes-ethyl acetate) to give the desired compound as a light yellowfoam (6.73 g, 91%). ¹H NMR (CDCl₃) 7.76 (t, J=8.0 Hz, 2H), 7.63 (dd,J=5.0, 8.5 Hz, 2H), 5.51, 5.16 (2d, J=16.0 Hz, 1H), 5.32, 5.28 (2d,J=16.5 Hz, 1H), 4.48, 4.40 (dd, J=5.0, 8.5 Hz, 1H), 3.56 (m, 1H), 3.43(m, 1H), 2.30 (m, 2H), 2.06 (m, 1H), 1.92 (m, 1H), 1.46, 1.43 (2s, 9H).Step 332b. To a solution of the compound from step 332a (6.73 g, 16.3mmol) in toluene (100 mL) was added ammonium acetate (25.1 g, 0.327 mol)and the resultant mixture was heated at 100° C. for 14 hours. Thevolatiles were evaporated and the residue was partitioned (EtOAc-aq.NaHCO₃). The organics were washed with brine, dried (Na₂SO₄), filteredand evaporated. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as a yellowfoam (6.10 g, 95%). ESIMS m/z=392.24, 394.24 [M+H]⁺. ¹H NMR (CDCl₃) 7.57(bs, 1H), 7.48 (m, 3H), 7.23 (s, 1H), 4.97 (m, 1H), 3.42 (m, 2H), 2.99(m, 1H), 2.16 (m, 2H), 1.97 (m, 1H), 1.46 (s, 9H).Step 332c. To a mixture of the compound from step 332b (1.00 g, 2.55mmol), bis(pinacolato)diboron (1.35 g, 5.33 mmol) and potassium acetate(0.640 g, 6.53 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh₃)₄ (0.147g, 0.128 mmol). The resultant mixture was degassed and heated at 80° C.under N₂ for 14 hours. The volatiles were evaporated and the residue waspartitioned (EtOAc-water). The organics were washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give thedesired compound as a light yellow solid (0.978 g, 87%). ESIMSm/z=440.39 [M+H]⁺. ¹H NMR (CDCl₃) 11.03, 10.55 (2s, 1H), 7.79 (m, 3H),7.45 (m, 1H), 7.26 (m, 1H), 4.97 (m, 1H), 3.41 (m, 2H), 3.06, 2.91 (2m,1H), 2.17 (m, 2H), 1.97 (m, 1H), 1.49 (s, 9H), 1.35 (s, 12H).Step 332d. To a mixture of the compound from step 318l (106 mg, 0.235mmol), the compound from step 332c (155 mg, 0.352 mmol) and NaHCO₃ (79mg, 0.94 mmol) in DME (5.2 mL) and H₂O (1.7 mL) was added Pd(PPh₃)₄ (14mg, 0.012 mmol). The resultant mixture was degassed and heated at 80° C.under N₂ for 3 hours. The volatiles were evaporated and the residue waspartitioned (EtOAc—H₂O). The organics were washed with brine, dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give the titlecompound as a light yellow solid (53 mg, 35%). ESIMS m/z=637.40 [M+H]⁺.

Example 333

Step 333a. Into a suspension of NaH (60%, 320 mg, 8 mmol) in DME (10 mL)was added 3-bromopropyltriphenylphosphonium bromide (1.86 g, 4 mmol).The resulting suspension was stirred at 70° C. for 6 hours before(S)-1-(tent-butoxycarbonyl)-4-oxopyrrolidine-2-carboxylic acid (508 mg,2 mmol) was added. The suspension was heated at 70° C. for another 20hours before being allowed to cool down and quenched with water. Thevolatile was evaporated. The residue was partitioned (H₂O-EtOAc). Theorganic phase was extracted with K₂CO₃ (1 M) twice. The combined aqueousphase was cooled in an ice-water bath. HCl (Conc.) was added to adjustthe pH to ˜3. The resulted mixture was extracted with EtOAc (*2). Thecombined organic phases were dried (Na₂SO₄) and concentrated to afford abrown oil (280 mg), which was used directly for the next step. ESIMSm/z=254.13 [M+H]⁺.Step 333b. Into a solution of the compound from step 333a (1.1 mmol atmost), 1,2-diamine-4-iodobenzene (257 mg, 1.1 mmol) and EDC.HCl (250 mg,1.3 mmol) in acetonitrile (6 mL) was added the DMAP (13 mg, 0.10 mmol).The resulting solution was stirred at room temperature for 16 h. Thevolatile was evaporated. The resultant oil was partitioned (H₂O-DCM).The organic phase was separated, dried (Na₂SO₄) and concentrated toafford a brown oil (1.10 g), which was used directly for the next step.Step 333c. The solution of the crude product from 333b (1.1 mmol atmost) in AcOH was heated at 55° C. for 6 hours. The volatile wasevaporated. The crude oil was partitioned between NaHCO₃ (aq) and EtOAc.The organic phase was separated, dried (Na₂SO₄) and concentrated. Theresidue was purified by flash column chromatography (silica,EtOAc-hexanes) to afford the desired compound as a yellow foam (68 mg,8% over three steps). ESIMS m/z=452.06 [M+H]⁺.Step 333d. A mixture of the compound from step 332b (0.559 g, 1.425mmol), trimethylsilylacetylene (0.60 ml, 4.275 mmol), CuI (28.5 mg,0.150 mmol) and Pd(PPh₃)₂Cl₂ (80.0 mg, 0.114 mmol) in Et₃N (15 mL) washeated at 80° C. under N₂ for 6 hours before being evaporated. Theresidue was purified by chromatography (silica, hexanes-ethyl acetate,with 1% Et₃N in ethyl acetate) to give the desired compound as a yellowfoam (0.484 g, 83%). ESIMS m/z=410.24 [M+H]⁺.Step 333e. A suspension of the compound from step 333d (0.484 g, 1.182mmol) and K₂CO₃ (0.408 g, 2.954 mmol) in methanol (12 ml) was stirred atrt for 3 hour. The volatiles were evaporated off. The residue waspurified by chromatography (silica, dichloromethane-ethyl acetate) togive the desired compound as a yellow foam (0.370 g, 93%). ESIMSm/z=338.24 [M+H]⁺.Step 333f. The title compound was prepared from the compound from step333c and the compound from step 333e using procedures similar to thatdescribed in step 318m. ESIMS m/z=661.31 [M+H]⁺.

Example 334

The title compound was prepared from the compound of example 333 usingprocedures similar to that described in example 83. ESIMS m/z=775.24[M+H]⁺.

Example 335

The title compound was prepared using procedures similar to thatdescribed in example 1. ESIMS m/z=647.25 [M+H]⁺.

Example 336

The title compound was prepared from the compound of example 335 usingprocedures similar to that described in example 83. ESIMS m/z=761.32[M+H]⁺.

Example 337

Step 337a. Into a solution of(+)-(3R,7aS)-tetrahydro-3-phenyl-3H,5H-pyrrolo[1,2-c]oxazol-5-one (2.10g, 9.85 mmol) in THF (60 mL) at −78° C. was added LiHMDS (1M in THF,39.4 mL, 39.4 mmol). The resultant mixture was kept at −78° C. for 30minutes before slow addition of allyl bromide (5.0 mL, 59.1 mmol). Thereaction was gradually warmed up to 0° C. and was quenched by aqueousNH₄Cl. The volatiles were evaporated and the residue was was partitioned(EtOAc—H₂O). The organics were dried (Na₂SO₄), filtered and evaporated.The residue was purified by flash column chromatography (silica,hexanes-ethyl acetate) to give the desired compound as a very lightyellow oil (2.30 g, 78%). ESIMS m/z=284.16 [M+H]⁺.Step 337b. Ozone was bubbled through a solution of the compound fromstep 337a (2.30 g, 8.11 mmol) in MeOH (85 mL) at −78° C. until theappearance of blue color. The extra O₃ was removed by the O₂ flow beforethe addition of NaBH₄ (2.46 g, 64.9 mmol) at −78° C. The resultantmixture was gradually warmed up to room temperature for 16 hours and wasquenched by 2M aqueous HCl to pH 5. The volatiles were evaporated andthe residue was was partitioned (EtOAc—H₂O). The organics were dried(Na₂SO₄), filtered and evaporated. The residue was purified by flashcolumn chromatography (silica, hexanes-ethyl acetate) to give thedesired compound as a colorless oil (1.61 g, 68%). ESIMS m/z=292.15[M+H]⁺.Step 337c. Into a mixture of the compound from step 337b (1.52 g, 5.21mmol), Ag₂O (1.81 g, 7.80 mmol) and KI (0.173 g, 1.04 mmol) in CH₂Cl₂(40 mL) was added TsCl (1.09 g, 5.73 mmol) in CH₂Cl₂ (20 mL) slowly. Theresultant mixture was stirred at room temperature for 24 hours beforebeing filtered through a pad of celite. The filtrates were evaporatedand the residue was purified by flash column chromatography (silica,hexanes-ethyl acetate) to give the desired compound as a colorless oil(1.38 g, 60%) with the recovery of the compound from step 26b (0.473 g,31%). ESIMS m/z=446.07 [M+H]⁺.Step 337d. Into a solution of the compound from step 337c (1.38 g, 3.11mmol) in THF (62 mL) was added NaH (60% in mineral oil, 0.187 g, 4.67mmol). The resultant mixture was stirred at room temperature for 24hours before being quenched by aqueous NH₄Cl. The volatiles wereevaporated and the residue was partitioned (EtOAc—H₂O). The organicswere dried (Na₂SO₄), filtered and evaporated. The residue was purifiedby flash column chromatography (silica, hexanes-ethyl acetate) to givethe desired compound as a colorless oil (0.726 g, 86%). ESIMS m/z=274.10[M+H]⁺.Step 337e. Into a solution of the compound from step 337d (0.726 g, 2.66mmol) in THF (50 mL) was added LiAlH₄ (1M in THF, 5.3 mL, 5.32 mmol).The resultant mixture was heated to 60° C. for 3 hours before beingquenched by sequential addition of H₂O (0.20 mL), 15% aqueous NaOH (0.20mL) and H₂O (0.60 mL) at 0° C. The mixture was passed through a pad ofcelite and the filtrates were evaporated. The residue was partitioned(EtOAc—H₂O) and the organics were dried (Na₂SO₄), filtered andevaporated. The residue was purified by flash column chromatography(silica, hexanes-ethyl acetate) to give the desired compound as acolorless oil (0.718 g). ESIMS m/z=262.21 [M+H]⁺.Step 337f. Into a mixture of compound from step 337e (2.66 mmol at most)and AcOH (0.30 mL, 5.32 mmol) in MeOH (16 mL) was added palladium (10 wt% on carbon, 54.8 mg). The resulting mixture was hydrogenated under 60psi H₂ at room temperature for 4 hours before being filtered through aplug of celite. The filtrate was concentrated to give the crude desiredcompound as a colorless oil (0.782 g). ESIMS m/z=172.17 [M+H]⁺.Step 337g. Into a mixture of the crude compound from step 337f (2.66mmol at most) and NaHCO₃ (1.79 g, 21.3 mmol) in 1,4-dioxane (10 mL) andH₂O (20 mL) was added Boc₂O (0.696 g, 3.19 mmol). The resultant mixturewas stirred at room temperature for 1 day before being evaporated todryness. The residue was partitioned (EtOAc—H₂O) and the organics weredried (Na₂SO₄), filtered and evaporated. The residue was purified byflash column chromatography (silica, hexanes-ethyl acetate) to give thedesired compound as a colorless oil (0.610 g, 3 step 85%). ESIMSm/z=272.26 [M+H]⁺.Step 337h. Into a solution of the compound from step 337g (0.610 g, 2.25mmol) in carbon tetrachloride (9 mL), CH₃CN (12 mL) and H₂O (15 mL) wereadded RuCl₃.XH₂O (9.3 mg, 45.0 μmol) and NaIO₄ (0.963 g, 4.50 mmol). Theresultant mixture was stirred at room temperature for 4 hours beforebeing partitioned (CH₂Cl₂—H₂O). The aqueous phase was acidified to pH 3and was extracted by CH₂Cl₂ for 3 times. The combined organics weredried (Na₂SO₄), filtered and evaporated to give the crude desiredcompound as a light brown foam (0.640 g). ESIMS m/z=286.24 [M+H]⁺.Step 337i. The crude desired compound was prepared from the crudecompound from step 337h and 1,2-diamino-4-iodobenzene using proceduressimilar to that described in step 1c. ESIMS m/z=502.19 [M+H]⁺.Step 337j. The desired compound was prepared from the crude compoundfrom step 337i using procedures similar to that described in step 1d.ESIMS m/z=484.21 [M+H]⁺.Step 337k. The title compound is prepared from the compounds of step337j and 3181 using procedures similar to that described in examples 318and 83.

Biological Activity 1. HCV Replicon Cell Lines

HCV replicon cell lines (kindly provided by R. Bartenschlager) isolatedfrom colonies as described by Lohman et. al. (Lohman et al. (1999)Science 285: 110-113, expressly incorporated by reference in itsentirety) and used for all experiments. The HCV replicon has the nucleicacid sequence set forth in EMBL Accession No.: AJ242651, the codingsequence of which is from nucleotides 1801 to 8406.

The coding sequence of the published HCV replicon was synthesized andsubsequently assembled in a modified plasmid pBR322 (Promega, Madison,Wis.) using standard molecular biology techniques. One replicon cellline (“SGR 11-7”) stably expresses HCV replicon RNA which consists of(i) the HCV 5′UTR fused to the first 12 amino acids of the capsidprotein, (ii) the neomycin phosphotransferase gene (neo), (iii) the IRESfrom encephalomyocarditis virus (EMCV) and (iv) HCV NS2 to NS5B genesand the HCV 3′UTR. Another replicon cell line (“Huh-luc/neo-ET”)described by Vrolijk et. al. (Vrolijk et. al. (2003) Journal ofVirological Methods 110:201-209, expressly incorporated by reference inits entirety) stably expresses HCV replicon RNA which consists of (i)the HCV 5′UTR fused to the first 12 amino acids of the capsid protein,(ii) the firefly luciferase reporter gene, (iii) the ubiquitin gene,(iv) the neomycin phosphotransferase gene (neo), (v) the IRES fromencephalomyocarditis virus (EMCV) and (vi) HCV NS3 to NS5B genes thatharbor cell culture adaptive mutations (E1202G, T12801, K1846T) and theHCV 3′UTR.

These cell lines are maintained at 37° C., 5% CO₂, 100% relativehumidity in DMEM (Cat# 11965-084, Invitrogen), with 10% fetal calf serum(“FCS”, Invitrogen), 1% non-essential amino acids (Invitrogen), 1% ofGlutamax (Invitrogen), 1% of 100× penicillin/streptomycin (Cat#15140-122, Invitrogen) and Geneticin (Cat# 10131-027, Invitrogen) at0.75 mg/ml or 0.5 mg/ml for 11-7 and Huh-luc/neo-ET cells, respectively.

2. HCV Replicon Assay—qRT-PCR

EC₅₀ values of single agent compounds and combinations are determined byHCV RNA detection using quantitative RT-PCR, according to themanufacturer's instructions, with a TAQMAN® One-Step RT-PCR Master MixReagents Kit (Cat# AB 4309169, Applied Biosystems) on an ABI Model 7500thermocycler. The TAQMAN primers to use for detecting and quantifyingHCV RNA obtained from Integrated DNA Technologies. HCV RNA is normalizedto GAPDH RNA levels in drug-treated cells, which is detected andquantified using the Human GAPDH Endogenous Control Mix (AppliedBiosystems, AB 4310884E). Total cellular RNA is purified from 96-wellplates using the RNAqueous 96 kit (Ambion, Cat# AM1812). Chemical agentcytotoxicity is evaluated using an MTS assay according to themanufacturer's directions (Promega).

3. HCV Replicon Assay—Luciferase

Since clinical drug resistance often develops in viral infectionsfollowing single agent therapies, there is a need to assess theadditive, antagonistic, or synergistic properties of combinationtherapies. We used the HCV replicon system to assess the potential useof the compound of the present invention or in combination therapieswith Interferon alpha, cyclosporine analogs and inhibitors targetingother HCV proteins. The acute effects of a single or combinations ofdrugs are studied in the “Huh-luc/neo-ET” replicon with each chemicalagent titrated in an X or Y direction in a 6 point two-fold dilutioncurve centered around the EC50 of each drug. Briefly, replicon cells areseeded at 7,000 cells per well in 90 ul DMEM (without phenol red,Invitrogen Cat.# 31053-036) per well with 10% FCS, 1% non-essentialamino acids, 1% of Glutamax and 1% of 100× penicillin/streptomycin andincubated overnight at 37° C., 5% CO₂, 100% relative humidity. 16-20 hafter seeding cells, test compounds previously solubilized and titratedin dimethyl sulfoxide (“DMSO”) from each X plate and Y plate are diluted1:100 in DMEM (without phenol red, Invitrogen Cat.# 31053-036) with 10%FCS, 1% non-essential amino acids, 1% of Glutamax and 1% of 100×penicillin/streptomycin and added directly to the 96-well platecontaining cells and growth medium at a 1:10 dilution for a finaldilution of compound and DMSO of 1:1000 (0.2% DMSO final concentration).Drug treated cells are incubated at 37° C., 5% CO₂, 100% relativehumidity for 72 hours before performing a luciferase assay using 100 ulper well BriteLite Plus (Perkin Elmer) according to the manufacturer'sinstructions. Data analysis utilizes the method published by Prichardand Shipman (Antiviral Research, 1990. 14:181-205). Using this method,the combination data are analyzed for antagonistic, additive, orsynergistic combination effects across the entire combination surfacecreated by the diluted compounds in combination.

The compounds of the present invention may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present invention inhibit HCV replicon and in anotherembodiment the compounds of the present invention inhibit NS5A.

The compounds of the present invention can be effective against the HCV1b genotype. It should also be understood that the compounds of thepresent invention can inhibit multiple genotypes of HCV. In oneembodiment compound of the present invention are active against the 1a,1b, 2a, 2b, 3a, 4a, and 5a genotypes. Table 12 shows the EC₅₀ values ofrepresentative compounds of the present invention against the HCV 1bgenotype from the above described qRT-PCR or luciferase assay. EC₅₀ranges against HCV 1b are as follows: A>1 nM; B 10-1000 nM; C<10 μM.

TABLE 12 Genotype-1b replicon EC₅₀ Example Range EC₅₀ Example Range EC₅₀Example Range EC₅₀ 83 C 5.7 pM 252 B 11.2 pM 300 C  4.4 pM 316 C 319 B321 B 323 C 9.2 pM 325 C  5.9 pM 327 C 329 C 331 B 13.7 pM 334 B 13.0 pM336 C 6.4 pM

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ring A and RingB are each independently absent or a monocyclic or polycyclic groupindependently selected from the group consisting of aryl, heteroaryl,heterocyclic, C₃-C₈ cycloalkyl, and C₃-C₈ cycloalkenyl, each optionallysubstituted; L is absent or selected from the group consisting ofoptionally substituted C₁-C₄ alkyl, optionally substituted C₂-C₄alkenyl, and optionally substituted C₂-C₄ alkynyl; wherein at least oneof Ring A, Ring B and L is present; G and J are each independently anoptionally substituted 5-membered heteroaryl or optionally substituted5/6-membered fused heteroaryl, wherein the 5-membered heteroarylcontains one or more nitrogen atoms, and wherein the 6-membered ring ofsaid 5/6-membered fused heteroaryl is attached to one of Ring A, L orRing B and is aryl or heteroaryl; X is independently N—OR¹, N—N(R¹)₂, orC(R²)₂; R¹ at each occurrence is independently hydrogen or optionallysubstituted C₁-C₄ alkyl; R² at each occurrence is independentlyhydrogen, halogen, optionally substituted C₁-C₄ alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl; alternatively,two R² groups can be taken together with the carbon atom to which theyare attached to form an optionally substituted C₃-C₈ cycloalkyl oroptionally substituted heterocyclic ring; R⁶ at each occurrence isindependently selected from the group consisting of optionallysubstituted O(C₁-C₈ alkyl), optionally substituted amino, C₁-C₈ alkyl,C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl,heterocyclic, aryl, and heteroaryl, each optionally substituted; Q isselected from:

R³ and R⁴ are each independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₈ alkyl, optionally substitutedC₂-C₈ alkenyl, and optionally substituted C₃-C₈ cycloalkyl;alternatively, R³ and R⁴ can be taken together with the carbon atom towhich they are attached to form optionally substituted C₃-C₈ cycloalkylor optionally substituted heterocyclic; R⁵ is independently hydrogen,optionally substituted C₁-C₈ alkyl, or optionally substituted C₃-C₈cycloalkyl; U is absent or independently selected from O, S, S(O), SO₂,NC(O)—(C₁-C₄ alkyl), C(O), protected carbonyl, OCH₂, OCH₂CH₂, SCH₂,SCH₂CH₂, C(R⁷)₂, C(R⁷)₂C(R⁷)₂, C═C(R²)₂, C═N—O(R¹) or C═N—N(R¹)₂; R⁷ ateach occurrence is independently selected from the group consisting ofhydrogen, halogen, cyano, hydroxy, O(C₁-C₄ alkyl), S(C₁-C₄ alkyl), aminooptionally substituted with one or two C₁-C₄ alkyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted C₃-C₈ cylcloalkyl, and optionally substituted C₁-C₄ alkyl;Alternatively two geminal R⁷ groups can be taken together with thecarbon atom to which they are attached to form a spiro, optionallysubstituted C₃-C₇ cycloalkyl, spiro, optionally substituted C₃-C₇cycloalkenyl or spiro, optionally substituted, 3- to 7-memberedheterocyclic; R^(7a) and R^(7b) at each occurrence are eachindependently selected from the group consisting of hydrogen, optionallysubstituted aryl, and optionally substituted C₁-C₄ alkyl; Alternatively,CHR^(7a)—U or CHR^(7b)—U can be taken together to form a group selectedfrom CH═CH, fused and optionally substituted C₃-C₈ cycloalkyl, fused andoptionally substituted aryl, or fused and optionally substitutedheterocyclic; and Yet alternatively, U, R^(7a), and R^(7b) can be takentogether with the carbon atoms to which they are attached to form abridged, optionally substituted C₄-C₇ cycloalkyl, a bridged, optionallysubstituted C₄-C₇ cycloalkenyl or a bridged optionally substituted, 4-to 7-membered heterocyclic ring.
 2. The compound of claim 1, wherein Gor J is selected from:

wherein each of said imidazolyl, benzimidazolyl or imidazopyridyl groupsare each optionally substituted; or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 2, wherein X is C(R²)₂; R⁶ is C₁-C₈alkyl optionally substituted with amino, hydroxy, protected amino, orO(C₁-C₄ alkyl); and Q is

wherein U is CH₂, CHF, CHMe, CF₂, C═CH₂, or C═CF₂; R^(7a) is hydrogen;and R^(7b) is hydrogen or methyl; or a pharmaceutically acceptable saltthereof.
 4. The compound of claim 2, wherein X is C(R²)₂; R⁶ is C₁-C₈alkyl optionally substituted with amino, hydroxy, protected amino, orO(C₁-C₄ alkyl); and Q is

wherein U is C(R⁷)₂, wherein the two geminal R⁷ groups are takentogether with the carbon to which they are attached to form a spirocyclopropyl or a spiro 5- or 6-membered heterocyclic and R^(7a) andR^(7b) are hydrogen; or alternatively U and R^(7b) are taken togetherwith the carbon to which they are attached to form a fused cyclopropyl,and R^(7a) is hydrogen; or yet alternatively U, R^(7a) and R^(7b) aretaken together with the carbon atoms to which they are attached to forma bridged C₄-C₇ cycloalkyl; or a pharmaceutically acceptable saltthereof.
 5. The compound of claim 3, wherein Ring A and Ring B are eachindependently absent, phenyl, monocyclic heteroaryl, bicyclic aryl, orbicyclic heteroaryl, each optionally substituted; or a pharmaceuticallyacceptable salt thereof.
 6. The compound of claim 4, wherein Ring A andRing B are each independently absent, phenyl, monocyclic heteroaryl,bicyclic aryl, or bicyclic heteroaryl, each optionally substituted; or apharmaceutically acceptable salt thereof.
 7. The compound of claim 5,wherein L is absent; Ring A and Ring B are each independently optionallysubstituted phenyl or optionally substituted monocyclic heteroaryl; or apharmaceutically acceptable salt thereof.
 8. The compound of claim 6,wherein L is absent; Ring A and Ring B are each independently optionallysubstituted phenyl or optionally substituted monocyclic heteroaryl; or apharmaceutically acceptable salt thereof.
 9. The compound of claim 5,wherein L is absent; one of Ring A and Ring B is optionally substitutedphenyl or optionally substituted monocyclic heteroaryl, and the other ofA and B is optionally substituted bicyclic aryl or optionallysubstituted bicyclic heteroaryl; or a pharmaceutically acceptable saltthereof.
 10. The compound of claim 6, wherein L is absent; one of Ring Aand Ring B is optionally substituted phenyl or optionally substitutedmonocyclic heteroaryl, and the other of Ring A and Ring B is optionallysubstituted bicyclic aryl or optionally substituted bicyclic heteroaryl;or a pharmaceutically acceptable salt thereof.
 11. The compound of claim5, wherein U is CH₂ or C═CH₂; Ring A is absent; Ring B is phenyl,monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl, eachoptionally substituted; and L is optionally substituted C₂-C₄ alkenyl oroptionally substituted C₂-C₄ alkynyl; or a pharmaceutically acceptablesalt thereof.
 12. The compound of claim 1, wherein the compound has theFormula (Ic-1) or (Ic-2):

and pharmaceutically acceptable salts thereof, wherein each R, R′, R″and R″′ is independently H, halogen, optionally substituted C₁-C₆-alkyl,optionally substituted C₁-C₆-alkoxy, or optionally substitutedC₁-C₆-alkyl-C(O)—.
 13. The compound of claim 1, wherein the compound hasthe Formula (Ic-3):

or a pharmaceutically salt thereof, wherein A^(a) is selected from thefollowing:


14. The compound of claim 1, wherein the compound has the Formula(Ic-4):

or a pharmaceutically acceptable salt thereof, wherein A^(a) is selectedfrom the following:


15. The compound of claim 1, wherein the compound has the Formula(Ic-5):

or a pharmaceutically acceptable salt thereof, wherein G^(g) is selectedfrom the following:


16. The compound of claim 1 selected from the group of compounds 1-337compiled in the following tables: Compounds 1-219.

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194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

Compounds 220-229.

Entry R R′ R″ U Entry R R′ R″ U 220 Me H H CH₂ 221 H H H CF₂ 222 Me H HS 223 H H H

224 H Me H CH₂ 225 H H H

226 H Ph H CH₂ 227 H H H

228 H H Ph CH₂ 229 H H H

Compounds 230-239.

Entry R R′ R″ Entry R R′ R″ 230 Me H H 231 H CO₂Me H 232 H F H 233 H HCO₂Me 234 H H F 235 H OMe H 236 H Cl H 237 H H OMe 238 H H Cl 239 H CF₃H

Compounds 240-249.

Entry R R′ R″ R′′′ Entry R R′ R″ R′′′ 240 F H H H 241 F F H H 242 Me H HH 243 Me Me H H 244 H H Me Me 245 H H Et Et 246 CF₃ H H H 247 CF₃ H CF₃H 248 Cl H H H 249 Cl H Cl H

Compounds 250-264.

Entry R 250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

Compounds 265-282.

Entry A^(a) 265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

Compounds 283-303.

Entry A^(a) 283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

Compounds 304-315.

Entry G^(g) Entry G^(g) 304

305

306

307

308

309

310

311

312

313

314

315

Compounds 316-337


17. A pharmaceutical composition comprising a compound or a combinationof compounds according to claim 1 or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier orexcipient.
 18. A method of inhibiting the replication of anRNA-containing virus comprising contacting said virus with atherapeutically effective amount of a compound or combination ofcompounds of claim 1, or a pharmaceutically acceptable salt thereof 19.A method of treating or preventing infection caused by an RNA-containingvirus comprising administering to a subject in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of claim 1, or a pharmaceutically acceptable salt thereof. 20.The method of claim 19, wherein the RNA-containing virus is hepatitis Cvirus.
 21. The method of claim 19, further comprising the step ofco-administering one or more agents selected from the group consistingof a host immune modulator, and an antiviral agent, or a combinationthereof.
 22. The method of claim 21, wherein the host immune modulatoris selected from the group consisting of interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, consensusinterferon, a cytokine, a vaccine and a vaccine comprising an antigenand an adjuvant.
 23. The method of claim 21, wherein the antiviral agentinhibits replication of HCV by inhibiting host cellular functionsassociated with viral replication.
 24. The method of claim 21, whereinthe antiviral agent inhibits the replication of HCV by targetingproteins of the viral genome.
 25. The method of claim 21 wherein saidantiviral agent inhibits a viral protein and/or a replication process,wherein said protein or process is selected from the group consisting ofhelicase, protease, polymerase, metalloprotease, NS4A, NS4B, NS5A,assembly, entry, and IRES.
 26. The method of claim 21, furthercomprising the step of co-administering an agent or combination ofagents that treat or alleviate symptoms of HCV infection, wherein saidsymptoms are cirrhosis of the liver, inflammation of the liver, or acombination thereof.
 27. The pharmaceutical composition of claim 17,further comprising an agent selected from interferon, pegylatedinterferon, ribavirin, amantadine, an HCV protease inhibitor, an HCVpolymerase inhibitor, an HCV helicase inhibitor, or an internal ribosomeentry site inhibitor.
 28. The composition of claim 17, furthercomprising a cytochrome P450 monooxygenase inhibitor or apharmaceutically acceptable salt thereof.
 29. The composition of claim28, wherein the cytochrome P450 mooxygenase inhibitor is ritonavir. 30.A method of co-administering to a subject in need of anti-hepatitis Cviral treatment comprising administering to said subject a cytochromeP450 monooxygenase inhibitor or a pharmaceutically acceptable saltthereof, and a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 31. A process of making a compound according to claim 1comprising: i) preparing a compound of Formula (II):

via a transition-metal catalyzed cross-coupling reaction; wherein: G, J,U, X, R¹, R³, R⁴, R⁵, R^(7a) and R^(7b) are as defined in claim 1; RingA¹ is absent, optionally substituted aryl or optionally substitutedheteroaryl; Ring B¹ is optionally substituted aryl or optionallysubstituted heteroaryl; L¹ is absent, optionally substituted C₂-C₄alkenyl or C₂-C₄ alkynyl; and Z^(a) and Z^(b) are each independently anamino protecting group or —C(O)—R⁶; ii) when Z^(a) or Z^(b) is an aminoprotecting group, fully or selectively deprotecting a compound ofFormula (II) to give the corresponding amine of Formula (III):

wherein Z^(c) is hydrogen, an amino protecting group or —C(O)—R⁶; iii)capping the released amino group of a compound of Formula (III) withLG-C(O)—R⁶, wherein LG is a leaving group; to give the compound ofFormula (IV):

wherein Z^(d) is an amino protecting group —C(O)—R⁶; and iv) repeatedreaction sequence of deprotecting and capping (step ii-iii) to give thecompound of Formula (V):